Clinical trial NCT02033993
Conditions: Urothelial Cancer
Sponsor: Canadian Cancer Trials Group
Start date: 2014-03-11; Completion date: 2020-10-28
Enrollment: 199 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the effects on urothelial cancer of nab-paclitaxel compared to paclitaxel to treat this disease.

This research is being done because currently there is no effective treatment for urothelial cancer that has progressed after prior chemotherapy.

Detailed description:
Nab-paclitaxel is a formulation of the chemotherapeutic drug paclitaxel that is combined with a human protein called albumin. In Canada, nab-paclitaxel is currently approved for the treatment of metastatic breast cancer. This drug has been tested in other cancers and has shown promising activity in lung cancer, melanoma and pancreatic cancer. Information from research studies suggests that nab-paclitaxel may be a useful treatment for urothelial cancer.

Arms: arm 1: Nab-Paclitaxel - 260mg/m2: q21 days arm 2: Paclitaxel - 175mg/m2: q21 days
Interventions: intervention 1: Nab-Paclitaxel intervention 2: Paclitaxel
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
ICF_001.pdf: 
 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
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SAMPLE Informed Consent Form 
 
A MULTICENTRE RANDOMIZED PHASE II TRIAL COMPARING NAB-PACLITAXEL TO 
PACLITAXEL IN PATIENTS WITH ADVANCED UROTHELIAL CANCER PROGRESSING ON 
OR AFTER A PLATINUM CONTAINING REGIMEN 
 
Trial Code: BL.12 
 
Researcher: Dr. ________________ 
 
Sponsor: NCIC Clinical Trials Group 
 
Le formulaire de consentement est disponible en français sur demande. 
 
Note to centre: If an REB approved French consent is not used at your institution you should remove the above statement. 
 
 
Emergency Contact Number (24 hours / 7 days a week): _________________________ 
 
Non-Emergency contact numbers are noted at the end of this document under the section 
heading “Contacts”.  
 
 
INTRODUCTION 
 
You are being invited to participate in a clinical trial (a type of study that involves research). 
Clinical trials only include participants who choose to take part. You are invited to participate in 
this trial because you have urothelial cancer for which you have already received 
chemotherapy. Your urothelial cancer has now progressed, which means it has worsened or 
relapsed (come back), and cannot be cured by radiation treatment or surgery. This consent form 
provides you with information to help you make an informed choice. Please read this document 
carefully and take your time in making your decision. You may find it helpful to discuss it with 
your friends and family. 
 
Taking part in this study is voluntary. You may choose not to take part or may leave the study at 
any time without giving a reason. Deciding not to take part or deciding to leave the study later 
will not result in any penalty or any loss of benefits to which you are entitled. If you decide to 
stop participating in the study, your doctor will discuss other options with you and continue to 
treat you with the best means available. 
 
Nab-paclitaxel is a formulation of the chemotherapeutic drug paclitaxel that is combined with a 
human protein called albumin. In Canada, nab-paclitaxel is currently approved for the treatment 
of metastatic breast cancer. This drug has been tested in other cancers and has shown 
promising activity in lung cancer, melanoma and pancreatic cancer. Information from research 
studies suggests that nab-paclitaxel may be a useful treatment for urothelial cancer.  
Current Version: 
AMENDMENT #2: 
2014-DEC-19 


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
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Health Canada, the regulatory body that oversees the use of drugs in Canada, has not 
approved the sale or use of nab-paclitaxel or paclitaxel to treat urothelial cancer, although they 
have allowed its use in this study. The research ethics board, who oversees the ethical conduct 
of research involving humans in your hospital/clinic, has reviewed and accepted this study.  
 
 
PURPOSE 
 
The purpose of this study is to compare the effects on you and your urothelial cancer of nab-
paclitaxel compared to paclitaxel to treat this disease. 
 
This research is being done because currently there is no effective treatment for urothelial 
cancer that has progressed after prior chemotherapy.  
 
Note to centre, please adjust this section to reflect standard or usual treatment in accordance with your local 
policy.  
 
 
ALTERNATIVE TREATMENTS  
 
You do not have to take part in this study in order to receive treatment/care; other options may 
include, but are not limited to: 
• 
no therapy at this time 
• 
palliative care or Best Supportive Care (BSC). This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly, but instead tries to improve how you feel. Best Supportive Care tries to keep 
you as active and comfortable as possible. 
• 
other experimental studies may be available if you do not take part in this study 
 
Please talk to your study doctor or usual cancer doctor (if different from the study doctor) about 
the known benefits and risks of these other options before you decide to take part in this study. 
Your cancer doctor can also discuss with you what will happen if you decide not to undertake 
any treatment at this time. 
 
 
EXPECTED NUMBER OF PARTICIPANTS 
 
About 199 people from Canada, Australia and New Zealand will take part in this study. 
 
This study should take three and a half years to complete and the results should be known in 
about five years. 
 
Your study doctor will be informed of the results of this study once they are known. 


 
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ASSIGNMENT TO A GROUP  
 
If you decide to participate then you will be "randomized" into one of the groups described 
below. Randomization means that you are put into a group by chance (like flipping a coin). 
There is no way to predict which group you will be assigned to. You will have an equal chance 
of being placed in either group. Neither you nor your doctor can choose what group you will be 
in.  
 
You will be told which treatment you are to get. 
 
For Group 1 (EXPERIMENTAL ARM): Nab-Paclitaxel 
 
If you are randomized to Group 1 you will be given the experimental drug nab-paclitaxel. Nab- 
paclitaxel will be given into one of your veins by needle every 21 days. The procedure will take 
about 1 hour. You will continue on drug indefinitely as long as you are responding and able to 
tolerate the drug well. The dose may be changed if you have side effects. 
 
Group 2 (CONTROL ARM): Paclitaxel  
 
If you are randomized to Group 2 you will be given the experimental drug paclitaxel. Paclitaxel 
will be given into one of your veins by needle every 21 days. The procedure will take about 4 
hours. You will continue on drug indefinitely as long as you are responding and able to tolerate 
the drug well. The dose may be changed if you have side effects. 
 
No matter which Group you are randomized to, antiemetics, drugs that are effective against 
vomiting and nausea, and other medications, such as steroids, may be given before you receive 
your treatment to try to prevent some of the possible side effects from treatment. 
 
 
NON-EXPERIMENTAL PROCEDURES (Screening Procedures) 
 
The following tests will be done at the hospital or clinic to make sure that you are eligible for this 
study:  
 
Some of these tests may have been done as part of your standard care, in which case the 
results of those tests may be used.  
• 
blood tests 
• 
physical examination 
• 
pregnancy test 
• 
chest x-ray 
• 
magnetic resonance imaging (MRI) – a scan that uses a strong magnet to produce pictures 
of areas inside the body such as organs and other tissue, and inside of bones. 
• 
computed tomography (CT) scan- a series of x-rays of the body from many angles that are 
turned into 3-dimensional pictures on a screen. CT scans often involve injecting a dye into 
your vein. 


 
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AMEND #1: 2014-APR-25; AMEND #2: 2014-DEC-19 
• 
bone scan 
 
Many of these tests will also be repeated during the study. Some of these tests may be done 
more frequently than if you were not taking part in this study.  
 
 
QUESTIONNAIRES 
 
You will be provided with questionnaires before starting this study, on days 5 to 7 of cycles 1 
and 2 (one cycle equals every 21 days), day 1 of cycle 4 and then on day 1 of every 4 cycles 
while you are receiving study treatment. If you come off study treatment, then you will be given 
the questionnaire at every 6 week clinic visit until your cancer gets worse and/or your doctor 
decides to give you another treatment. The purposes of these questionnaires are to understand 
how your treatment and illness affects your quality of life. These questionnaires will each take 
about 10 minutes to complete.  
 
In addition, you will be asked to complete a health and demographic questionnaire around the 
time you start treatment. This questionnaire takes around 20 minutes to complete. The purpose 
of this questionnaire is to help researchers understand how different factors (such as your family 
history, and information about your life), may relate to bladder cancer. This includes trying to 
understand which factors might influence the likelihood of getting bladder cancer, predict who 
can benefit most from or how people respond to treatment, and effect quality of life. This 
information may also be used to help understand how the trial results relate to the general 
population. These questionnaires ask for information on where you were born, your medical 
history, your family’s medical history, information on your exposure to cigarettes and alcohol 
use, physical activity, past and present occupations, educational history, and marital status. This 
questionnaire also collects information on race and ethnicity as well as other characteristics of 
individuals because these characteristics may influence how people respond to different 
medications.The identification on the questionnaire will include your participant code, which 
includes your initials. The questionnaires will be sent to NCIC Clinical Trials Group.  
 
The information you provide is for research purposes only and will remain strictly confidential. 
Some of the questions are personal; you can choose not to answer these if you wish. The 
individuals (e.g. doctors, nurses, etc.) who are not involved in the study will not review your 
responses to these questions—if you wish them to know this information please bring it to their 
attention.  
 


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
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AMEND #1: 2014-APR-25 
Optional Sample Collection and Banking 
 
The researchers doing this study are interested in doing additional research now or in the future 
on the samples collected from you. You will be given an additional optional study consent form 
to read and sign if you wish to give permission for the samples to be banked (stored) for future 
research purposes. You may decide not to participate in the "optional" study and still participate 
in this main study. 
 
 
RESPONSIBILITIES 
 
If you choose to participate in this study, you will be expected to: 
• 
Tell your study doctor about your current medical conditions; 
• 
Tell your study doctor about all prescription and non-prescription medications and 
supplements, including vitamins and herbals, and check with your study doctor before 
starting, stopping or changing any of these. This is for your safety as these may interact with 
the treatment you receive on this study. Tell your study doctor if you are thinking about 
participating on another research study; 
• 
Return any questionnaires to the study doctor that you take home to complete; 
• 
Tell your study doctor if you become pregnant or father a child while participating on this 
study; 
• 
Patients should not use St. John’s Wort as an herbal medicine during study treatment. 
 
 
LENGTH OF PARTICIPATION 
 
Your treatment with nab-paclitaxel, if you are randomized to Group 1 (Experimental Arm), or 
paclitaxel, if you are randomized to Group 2 (Control Arm), will continue until your doctor feels 
you are no longer benefiting from your treatment.  
 
Note to centres: Centres should indicate the overall length of time required beyond that of the standard or usual care 
at the Centre - specifying the difference in the number of visits and the length of time for each visit plus the time 
needed to complete questionnaires or diaries. 
 
No matter which group you are randomized to, and even if you stop treatment early, we would 
like to keep track of your health for the rest of your life to look at the long-term effects of your 
participation on this study. 


 
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EARLY END TO PARTICIPATION 
 
The researchers can take you off the study treatment early for reasons such as: 
• 
The treatment does not work for you and your cancer gets worse. 
• 
You are unable to tolerate the study treatment. 
• 
New information shows that the study treatment is no longer in your best interest. 
• 
Your doctor no longer feels this is the best treatment for you. 
• 
The NCIC CTG decides to stop the study. 
• 
If you become pregnant. 
 
 
RISKS OF PARTICIPATION 
 
Participating on this study will put you at risk for the side effects listed below. You should 
discuss these with your doctor. As with any experimental drug additional unexpected and 
sometimes serious side effects are a possibility. 
 
Your doctor will watch you closely to see if you have side effects. When possible, other drugs 
will be given to you to make side effects less serious and more tolerable. Many side effects go 
away shortly after chemotherapy is stopped but in some cases side effects can be serious, long-
lasting, permanent, or may even cause death. 
 
 
Risks and side effects related to the experimental drug NAB-PACLITAXEL we are studying 
include: 
 
Very likely (21% or more): 
• 
nausea and vomiting (If needed, nausea medication will be prescribed before and during 
treatment.) 
• 
lowering of blood cell counts (red cells, white cells and platelets) which could increase your 
risk of developing anemia, infection or bleeding/ bruising  
• 
diarrhea 
• 
constipation 
• 
anorexia 
• 
dehydration 
• 
hair loss 
• 
fatigue and/or tiredness 
• 
general weakness, loss of strength 
• 
joint and/or muscle pain 
• 
infection including pneumonia, blood infection (sepsis), shingles, urinary tract infection, 
upper respiratory infection, sore throat, cold sores, sinusitis, yeast infection of the mouth 
(thrush). Rarely infections may be serious and or life threatening 


 
CONSENT FORM DATE: 2013-DEC-12 
 
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Admin Update #1: 2014-JAN-10; AMEND #2: 2014-DEC-19 
• 
abnormal heart rhythm seen in electrocardiogram (ECG) which could rarely be a sign of a 
more severe heart problem 
• 
numbness, tingling in hands and feet, possibly with strength reduced (may be severe) 
• 
abnormal liver function as seen by blood tests (in rare cases this can be life threatening) 
 
Less likely (5 – 20%): 
• 
fever 
• 
shortness of breath 
• 
cough 
• 
rash or itchiness 
• 
swelling of legs, arms, hands or feet due to accumulation of fluid 
• 
inflammation or sores in the mouth and lining of the intestine which could become severe  
• 
low blood pressure (hypotension) 
• 
changes in vision including blurred vision and less likely, inflammation of the cornea or fluid 
accumulation leading to decreased vision. These are generally reversible but rarely can lead 
to permanent loss of vision. 
 
Rarely (1 – 4%): 
• 
pain (itching, swelling, redness) at the injection and/or catheter sites 
• 
nail changes (changes in colour of nail bed) 
• 
allergic reactions (swelling of the face, lips or tongue, difficulty breathing, rash, flushing or 
fainting) (very rarely can be life threatening). 
• 
abnormal heart beat (faster, slower, or irregular), chest pain or heart attack or heart failure. 
• 
high blood pressure (hypertension) 
• 
abnormal kidney function seen by blood tests 
• 
inflammation of the colon  
• 
blockage of the intestine, formation of a hole in the lining of the intestine 
• 
inflammation of the pancreas  
• 
severe life threatening damage to the lungs which can lead to inflammation and fluid in the 
lungs and scarring of lung tissue 
• 
poor functioning of your brain due to changes in the salts in your blood. 
• 
stroke 
• 
confusion, dizziness/light-headedness 
• 
depression, mood changes 
• 
weakness or loss of function of a muscle caused by damage to a nerve  
• 
serious skin disorders such as Stevens-Johnson syndrome, a condition that affects your 
skin and mucous membranes which begins with flu-like symptoms followed by a painful red 
or purplish rash that spreads and blisters and may be followed by shedding of the top layer 
of skin 
 
Risks and side effects related to the experimental drug PACLITAXEL we are studying include: 
 
Very likely (21% or more): 
• 
nausea and vomiting (If needed, nausea medication will be prescribed before and during 
treatment.) 
• 
diarrhea 


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
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Admin Update #1: 2014-JAN-10; AMEND #2: 2014-DEC-19 
• 
lowering of blood cell counts (red cells, white cells and platelets) which could increase your 
risk of developing anemia, infection or bleeding/ bruising  
• 
inflammation or sores in the mouth and lining of the intestine which could become severe 
• 
allergic reactions (swelling of the face, lips or tongue, difficulty breathing, shortness of 
breath, a fast heart rate, changes in blood pressure, excessive sweating, chills, pain, rash, 
flushing or fainting). 
• 
numbness, tingling in hands and feet, possibly with strength reduced (may be severe)  
• 
fatigue and/or tiredness 
• 
general weakness, loss of strength 
• 
joint and/or muscle pain 
• 
infection including pneumonia, blood infection (sepsis), shingles, urinary tract infection, 
upper respiratory infection, sore throat, cold sores, sinusitis, yeast infection of the mouth 
(thrush). Rarely infections may be serious and/or life threatening.  
• 
abnormal heart rhythm seen in electrocardiogram (ECG) which could rarely be a sign of a 
more severe heart problem  
• 
abnormal liver function as seen by blood tests (in rare cases this can be life threatening) 
• 
hair loss 
 
Less likely (5 – 20%): 
• 
low blood pressure (hypotension) 
• 
fever 
• 
constipation 
• 
abnormal kidney function seen by blood tests 
• 
pain (itching, swelling, redness) at the injection and/or catheter sites 
• 
swelling of legs, arms, hands or feet due to accumulation of fluid 
• 
changes in vision including blurred vision and less likely, inflammation of the cornea or fluid 
accumulation leading to decreased vision. These are generally reversible but rarely can lead 
to permanent loss of vision. 
 
Rarely (1 – 4%): 
• 
abnormal heart beat (faster, slower, or irregular), chest pain or heart attack or heart failure. 
• 
fainting 
• 
high blood pressure (hypertension) 
• 
nail changes (changes in colour of nail bed) 
• 
inflammation of the colon  
• 
blockage of the intestine, formation of a hole in the lining of the intestine 
• 
inflammation of the pancreas  
• 
severe life threatening damage to the lungs which can lead to inflammation and fluid in the 
lungs and scarring of lung tissue 
• 
hearing loss  
• 
weakness or loss of function of a muscle caused by damage to a nerve  
• 
abnormal brain function, seizures 
• 
dehydration 
• 
serious skin disorders such as Stevens-Johnson syndrome, a condition that affects your 
skin and mucous membranes which begins with flu-like symptoms followed by a painful red 
or purplish rash that spreads and blisters and may be followed by shedding of the top layer 
of skin 


 
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NCIC CTG TRIAL: BL.12 
 
 
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It is possible that other drugs (prescription and non-prescription drugs), vitamins, or herbals can 
interact with the drugs used in this study. This can result in either the drugs not working as 
expected or result in severe side effects. 
 
Long term effects of the chemotherapy used in this study include an increased risk of 
developing other cancers. 
 
Some cancer treatments such as chemotherapy (including nab-paclitaxel and paclitaxel) or 
other drugs increase the risk of blood clots in your veins. Please tell your doctor if you have any 
new swelling in a leg or arm or have a sudden problem with your breathing. These may be signs 
of a clot forming or a clot moving to your lungs. Rarely, blood clots can be fatal.  
 
A Data Safety Monitoring Board, an independent group of experts, will be reviewing the data 
from this research throughout the study. 
 
 
REPRODUCTIVE RISKS 
 
Nab-paclitaxel and paclitaxel may harm an unborn baby (fetus). You must not become pregnant 
or father a baby while taking nab-paclitaxel and paclitaxel and for 30 days after the last dose. 
Your study doctor will discuss methods with you to ensure that you do not become pregnant or 
father a baby during the study.  
 
Women should not nurse (breastfeed) a baby while taking study treatment and for 30 days after 
the last dose because the drugs used in this study might be present in breast milk and could be 
harmful to a baby.  
 
If you become pregnant or father a child during this study or for 30 days after you stop taking 
the study drug, then you should immediately notify your study doctor. Your study doctor will let 
the sponsor know about the pregnancy.  
 
If you become pregnant, the researchers or sponsors for this study will access information on 
the outcome of the pregnancy (the child’s health etc.). This information will be gathered from 
your medical/study record. This may also involve contacting you to ask about the health of your 
child. We may also ask to contact the child’s father to get information related to the pregnancy. 
If you become pregnant and do not want the researchers/sponsors to collect this information, 
you must let your study doctor know. 
 
If you father a child, the researchers or sponsor for this study will ask to contact the child’s 
mother to collect information on the outcome of the pregnancy (the child’s health, etc.). Your 
partner will be given a separate consent document to sign to give permission for the collection 
of this information, if a pregnancy should happen. 
 
Some of the drugs used in this study may make you unable to have children in the future. Your 
study doctor will discuss this with you. 
 
 
BENEFITS 
 
If you agree to take part in this study, there may or may not be direct benefit to you. We hope 
the information learned from this study will help other patients in the future.  


 
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CONFIDENTIALITY 
 
Records identifying you at this centre will be kept confidential and, to the extent permitted by the 
applicable laws, will not be disclosed or made publicly available, except as described in this 
consent document. 
 
Qualified representatives of the following organizations may look at your original (identifiable) 
medical/clinical study records at the site where these records are held, for quality assurance (to 
check that the information collected for the study is correct and follows proper laws and 
guidelines). 
 
• 
NCIC Clinical Trials Group (NCIC CTG), the research group coordinating this study 
• 
The research ethics board who oversees the ethical conduct of this study in your 
hospital/clinic  
• 
Celgene, the company which makes the drug nab-paclitaxel 
• 
Health Canada (because they oversee the use of drugs in Canada) 
• 
Other regulatory authorities (because they oversee the use of new drugs in other countries) 
 
Qualified representatives of the following organizations, in addition to those listed above, may 
receive information related to the study from your medical/clinical study records, containing your 
participant code, initials, sex, and date of birth, for quality assurance and data analysis.  
 
Note to centres: If there is planned disclosure of personal identifiers, or if they are used on any research-
related information/documents, or if they are part of the unique identifier, this must be justified in the REB 
application and approved. Please ensure that you are aware of your local REB’s and your centre’s 
policies with respect to the disclosure of personal identifiers; specifically date of birth and initials. If the 
REB or the centre mandates the disclosure only of partial date of birth (year/month), and/or of 
scrambled/coded initials, this will be accepted by NCIC CTG. 
 
Studies involving humans now routinely collect information on race and ethnicity as well as 
other characteristics of individuals because these characteristics may influence how people 
respond to different medications. Providing information on your race or ethnic origin is voluntary. 
Your name or other information that may identify you will not be used: 
• 
Australian Therapeutic Goods Administration (because they oversee the use of drugs in 
Australia) 
• 
New Zealand Ministry of Health (because they oversee the use of drugs in New Zealand) 
• 
Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) 
• 
NHMRC Clinical Trials Centre 
 
If the results of this study are published, your identity will remain confidential. It is expected that 
the information collected during this study will be used in analyses and will be published/ 
presented to the scientific community at meetings and in journals. This information may also be 
used as part of a submission to regulatory authorities around the world to support the approval 
of drugs used in this research. 


 
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All of the organizations listed in the above confidentiality sections are required to have strict 
policies and procedures to keep the information they see or receive about you confidential, 
except where disclosure may be required by law. The study doctor will ensure that any personal 
health information collected for this study is kept in a secure and confidential location as 
required by law. There are federal and provincial laws that these organizations must comply 
with to protect your privacy. 
 
Even though the likelihood that someone may identify you from the study data is very small, it 
can never be completely eliminated.  
 
A copy of the consent form that you sign to enter the study may be included in your health 
record/hospital chart. 
 
Your family doctor will be informed that you are taking part in a study so that your study doctor 
and your family doctor can provide proper medical care. 
 
Any information sent outside of Canadian borders may increase the risk of disclosure of 
information because the laws in those countries dealing with protection of information may not 
be as strict as in Canada. However, all study data and/or samples, that is transferred outside of 
Canada will be coded (this means it will not contain your personal identifying information such 
as your name, address, medical health number or contact information). Any information will be 
transferred in compliance with all relevant Canadian privacy laws. By signing this consent form, 
you are consenting to the disclosure of your coded information to organizations located outside 
of Canada. 
 
Registration of Clinical Trials 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov. 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. 
 
 
COSTS 
 
The study drug, nab-paclitaxel, will be given to you free of charge unless the following occurs: 
• 
You stop participating on this study. 
• 
The drug is no longer provided for this study. 
- 
If this occurs, you or your insurance company may have to pay for the drug. Your study 
doctor will discuss these options with you, as well what will happen if there is no more 
drug available. 
 
If a problem with getting nab-paclitaxel occurs, your study doctor will talk to you about these 
options.  
 
The costs of your medical treatment will be paid for by your provincial medical plan to the extent 
that such coverage is available. There may be extra costs that are not covered by your medical 
plan that you will have to pay yourself, some examples may be physiotherapy or certain pain 
medications. 


 
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Taking part in this study may result in added costs to you (i.e. transportation, parking, meals, or 
unpaid leave from work). You may have to pay for medication prescribed to treat or prevent side 
effects, and you may have to visit the hospital more often than if you were not participating in 
this study 
 
 
COMPENSATION  
 
You will not be paid for taking part in this study. 
 
It is possible that the research conducted using your study data may eventually lead to the 
development of new diagnostic tests, new drugs or other commercial products. There are no 
plans to provide payment to you if this happens. 
 
In the case of research-related side effects or injury, medical care will be provided by your 
doctor or you will be referred for appropriate medical care.  
 
Although no funds have been set aside to compensate you in the event of injury or illness 
related to the study treatment or procedures, you do not give up any of your legal rights for 
compensation by signing this form. This consent form does not relieve the investigator, the 
hospital, the sponsor, and their agents from their legal and professional responsibilities. 
 
 
RIGHTS 
 
If you decide to stop participating in the study, your doctor will discuss other options with you 
and continue to treat you with the best means available.  
 
You will be told, in a timely manner, about new information that may be relevant to your 
willingness to stay in this study. 
 
You may withdraw your permission to use your personal health information for this study at any 
time by letting the study doctor know. However, this would also mean that you withdraw from 
the study. Your study data that was recorded before you withdrew will be used but no 
information will be collected or sent to the sponsor after you withdraw your permission.  
 
Your rights to privacy are legally protected by federal and provincial laws that require 
safeguards to ensure that your privacy is respected. 
 
By signing this form you do not give up any of your legal rights against the investigators, 
sponsor or involved institutions for compensation, nor does this form relieve the investigators, 
sponsor or involved institutions of their legal and professional responsibilities. 
 
You will be given a copy of this signed and dated consent form prior to participating in this 
study. 


 
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CONFIDENTIAL 
CONFLICT OF INTEREST 
Note to centres: Please include details of any actual or potential conflict of interest concerning this study.  
 
This centre is receiving funds from the NCIC Clinical Trials Group to help offset the costs of 
conducting this research. NCIC CTG is a non-profit research group based on donated support. 
The researchers, this centre, and the NCIC CTG will not receive any direct benefit for 
conducting this study. 
 
 
CONTACTS 
 
If you have questions about taking part in this study, or if you suffer a research-related injury, 
you should talk to your study doctor. Or, you can meet with the doctor who is in charge of the 
study at this institution. That person is: 
 
 
____________________________ 
_________________________ 
Name 
Telephone  
 
 
If you have questions about your rights as a participant or about ethical issues related to this 
study, you can talk to someone who is not involved in the study at all. That person is: 
 
 
____________________________ 
_________________________ 
Name 
Telephone  
 


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
CONFIDENTIAL 
Page 14 of 18 
CONFIDENTIAL 
SIGNATURES 
 
• 
All of my questions have been answered, 
• 
I understand the information within this informed consent form, 
• 
I allow access to my medical records as explained in this consent form, 
• 
I do not give up any of my legal rights by signing this consent form, 
• 
I agree to take part in this study. 
 
 
____________________________ ______________________ 
_________________ 
Signature of Participant 
PRINTED NAME 
Date 
 
 
____________________________ ______________________ 
_________________ 
Signature of Person Conducting  
PRINTED NAME & ROLE 
Date 
the Consent Discussion 
 
NCIC CTG Participant Code: _____________________ 
 
 
Complete the following section only if the participant is unable to read or requires an oral 
translation: 
 
• 
The informed consent form was accurately explained to, and apparently understood by, the 
participant, and 
• 
Informed consent was freely given by the participant 
 
 
____________________________ ______________________ 
_________________ 
Signature of Impartial  
PRINTED NAME 
Date 
Witness/Translator 
(If participant were unable to  
read/required an oral translation) 
 
 
Please note: More information regarding the assistance provided during the consent process 
should be noted in the medical record for the participant if applicable, noting the role or 
relationship of the impartial witness. 
 
Note to Centres: When sending a signed copy to the NCIC CTG, the participant's printed name and the 
bottom half of their written signature, must be blacked out leaving only the upper portion of the signature 
visible but not identifiable (for verification that a signature was applied). 


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
CONFIDENTIAL 
Page 15 of 18 
CONFIDENTIAL 
SAMPLE -OPTIONAL - Informed Consent Form 
 
 
A MULTICENTRE RANDOMIZED PHASE II TRIAL COMPARING NAB-PACLITAXEL TO 
PACLITAXEL IN PATIENTS WITH ADVANCED UROTHELIAL CANCER PROGRESSING ON 
OR AFTER A PLATINUM CONTAINING REGIMEN 
 
Trial Code: BL.12 
 
Researcher: Dr. ________________ 
 
Sponsor: NCIC Clinical Trials Group 
 
Le formulaire de consentement est disponible en français sur demande. 
 
Note to centre: If an REB approved French consent is not used at your institution you should remove the above statement. 
 
 
Tissue and Blood Collection and Banking 
 
 
Optional tissue banking: The researchers doing this study are interested in doing research 
studies on tissue samples from your diagnostic cancer specimen to better understand the 
nature of cancer and how patients respond to treatment. The research that may be done with 
your tissue may not directly benefit you. It may help people in the future who have the same 
kind of cancer as you have. If you wish to support such research, you may choose to have your 
tissue stored at a central tissue bank for use now or in the future. This storage of tissue for 
future use is called “banking”. The “banking” of this tissue is an optional part of this study. You 
may refuse to have your tissue banked and still may take part in the main study. If you agree to 
have the tissue stored for future research, please read and sign this consent form, which deals 
specifically with tissue banking for future research. 
 
 
WHAT IS INVOVED IN OPTIONAL TISSUE BANKING? 
 
If you agree to donate your tissue, the samples collected will be from your cancer and some of 
the normal tissue surrounding your cancer that has already been removed by biopsy or surgery. 
No further surgeries or biopsies are needed for this purpose.  
 
Any tissue collected will be stored at a central tissue bank (a facility where tissues are stored for 
future research) located at Queen’s University in Kingston, Ontario. The samples will be kept 
indefinitely, or until they are returned to the hospital where you had your surgery or biopsy. 
Tissue will be used for research purposes only and will not be sold. The research done with 
your tissue may or may not help develop commercial products or tests. There are no plans to 
provide payment to you if this happens.  


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
CONFIDENTIAL 
Page 16 of 18 
CONFIDENTIAL 
 
AMEND #1: 2014-APR-25 
Optional blood banking: The researchers doing this study are interested in doing research on 
blood samples collected at the same time as your routine blood tests. These blood samples 
may help us understand who will benefit the most from this type of treatment. The banking of 
these samples is an optional part of this study. You may refuse to have your samples banked 
and still may participate in the main study.  
 
If you agree to donate your samples, they will be taken at the same time as your study related 
tests. This means 2 extra 5 ml (1 teaspoon) blood samples will be taken with a needle from a 
vein in your arm. The needles used to take blood might be uncomfortable. You might get a 
bruise, or rarely, an infection at the site of the needle puncture. 
 
Any blood samples collected will be stored at a central tissue bank (a facility where tissues, 
including tumours, blood and urine, are stored for future research) located at Queen’s University 
in Kingston, Ontario. The samples will be kept until they are used up. The samples will be used 
for research purposes only and will not be sold. The research done with your samples may or 
may not help develop commercial products or tests. There are no plans to provide payment to 
you if this happens.  
 
 
WHAT ARE YOUR RIGHTS AS A PARTICIPANT? 
 
Taking part in the tissue/ blood collection and banking part of this study is voluntary. You may 
choose not to take part, or may at any time withdraw your consent for this portion of the study 
and ask that the collected tissue / blood samples not be used. Deciding not to take part, or 
deciding to withdraw your consent for this portion of the study later, will not result in any penalty 
or loss of benefits to which you are entitled. If you decide to stop participating, and no longer 
want your tissue and/or blood samples to be used in this research, you should tell your doctor. 
Your doctor will notify the NCIC Clinical Trials Group (NCIC CTG) who will ensure the samples 
are destroyed (blood) or returned to the hospital where you had your original biopsy or surgery 
(tissue). If tests have already been done on your sample and included in an analysis or 
publication, it will not be possible to withdraw these. 
 
All the information provided in the main study consent form about confidentiality, costs, your 
rights as a participant, and who to contact with questions, applies to this consent form as well. 
 
 
HOW WILL THE IDENTITY OF MY SAMPLES BE PROTECTED? 
 
The identification that will be on your tissue samples kept in the bank may include your 
participant code, pathology identification number, initials and tumour bank code. The 
identification on blood samples may include your participant code and initials.  Samples will be 
given only to researchers whose proposals have been approved by the NCIC Clinical Trials 
Group and who are bound by a confidentiality agreement. Any research done on your samples 
will have been approved by a research ethics board. A research ethics board oversees the 
ethical conduct of a study, including protection of patient rights, confidentiality and safety. 
Tissue used for research is identified only by a special code to protect your identity and privacy. 


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
CONFIDENTIAL 
Page 17 of 18 
CONFIDENTIAL 
Reports about any research done with your samples will not be given to you or your doctor. 
These reports will not be put in your medical records. The research using your samples will not 
affect your care. 
 
In the future, people who do research with your sample may need to know more about your 
health. While the researchers coordinating this study may give them reports about your health, 
they will not give them your name, address, phone number or any other information that will let 
them know who you are. 
 
 
WILL GENETIC TESTING BE DONE ON MY TISSUE SAMPLES? 
 
All cancers are caused by changes in our genes or by changes in when or how these genes are 
expressed. NCIC CTG does not consider the study of changes in the genetic material of cancer 
cells to be “genetic research”, as these changes are acquired after you are born and not passed 
on in families This type of testing may be done on your samples if you agree to allow your 
samples to be banked for future research.  
 
Some changes in genes that are inherited may determine the way a person will respond to 
treatment. These changes may also determine what kind of side effects a person will have when 
they receive different kinds of treatment. These genetic changes do not cause cancer or other 
diseases and the study of these changes is not considered by the NCIC CTG to be “genetic 
testing”. This type of testing may be done on your samples if you agree to allow your samples to 
be banked for future research.  
 
Some cancers are a result of genetic changes that are inherited (passed on in families). Some 
genes that are inherited may determine a person’s chance of developing a particular disease, 
including cancer. Studies to look for these inherited genes that may cause cancer or other 
diseases are considered “genetic testing”. As part of future studies, researchers may want to 
study the genetic material that is inherited through families and that may cause cancer or other 
diseases. This type of testing may be done on your samples if you agree to allow your samples 
to be used for future “genetic testing”.  
 
Participating in “genetic testing” (testing for inherited genes that may cause cancer or other 
diseases) can involve risks for participants and their families. If you are identified as belonging 
to a high-risk group for developing a specific disease it could affect employment, health or life 
insurance, or might alter decisions about having children. This is why “genetic testing” results 
are not given to you, they are not put into your medical records and every effort is made to 
protect the privacy and confidentiality of these results. The chance of genetic test results being 
released in a way that can be linked to you is very small, however you should be aware of the 
risks. If you do not wish to have your samples used for “genetic testing”, you may indicate your 
wish at the end of this consent form. 
 


 
CONSENT FORM DATE: 2013-DEC-12 
 
NCIC CTG TRIAL: BL.12 
 
 
Version date and/or REB approval date of this form: ___________________________ 
 
CONFIDENTIAL 
Page 18 of 18 
CONFIDENTIAL 
SIGNATURES 
 
 I agree to allow tissue samples from my tumour and some of the normal tissue surrounding 
my tumour to be collected for the purposes described here. 
 I do not agree to allow tissue samples from my tumour and some of the normal tissue 
surrounding my tumour to be collected for the purposes described here. 
 
 I agree to allow blood samples to be collected for the purposes described here. 
 I do not agree to allow blood samples to be collected for the purposes described here. 
 
 I agree to allow my samples to be used for genetic testing to see if my cancer may be 
hereditary. 
 I do not agree to allow my samples to be used for genetic testing to see if my cancer may 
be hereditary. 
 
PLEASE CHECK THE APPROPRIATE BOXES ABOVE BEFORE SIGNING 
 
 
____________________________ ______________________ 
_________________ 
Signature of Participant 
PRINTED NAME 
Date 
 
 
____________________________ ______________________ 
_________________ 
Signature of Person Conducting  
PRINTED NAME & ROLE 
Date 
the Consent Discussion 
 
NCIC CTG Participant Code: _____________________ 
 
 
Complete the following section only if the participant is unable to read or requires an oral 
translation: 
• 
The informed consent form was accurately explained to, and apparently understood by, the 
participant, and 
• 
Informed consent was freely given by the participant 
 
 
____________________________ ______________________ 
_________________ 
Signature of Impartial  
PRINTED NAME 
Date 
Witness/Translator 
(If participant were unable to  
read/required an oral translation) 
 
Please note: More information regarding the assistance provided during the consent process 
should be noted in the medical record for the participant if applicable, noting the role or 
relationship of the impartial witness. 
 
Note to Centres: When sending a signed copy to the NCIC CTG, the participant's printed name and the 
bottom half of their written signature, must be blacked out leaving only the upper portion of the signature 
visible but not identifiable (for verification that a signature was applied). 

Prot_002.pdf: 
 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION 
 
 
ADMINISTRATIVE UPDATE #1: 2017-JUL-05 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
RANDOMIZED PHASE II STUDY COMPARING TWO DIFFERENT SCHEDULES OF 
PALBOCICLIB PLUS SECOND LINE ENDOCRINE THERAPY IN WOMEN WITH ESTROGEN 
RECEPTOR POSITIVE, HER2 NEGATIVE ADVANCED/METASTATIC BREAST CANCER 
(PALESTRA) 
 
CCTG Protocol Number: MA.38 
 
 
STUDY CHAIR: 
Anil Abraham Joy 
 
 
TRIAL COMMITTEE: 
Karen Gelmon 
 
 
Tim Whelan 
 
 
Mihaela Mates 
 
 
Christine Desbiens 
 
 
Mark Clemons 
 
 
Sara Taylor 
 
 
Janine Lombard 
 
 
SENIOR INVESTIGATOR: 
Wendy Parulekar 
 
 
BIOSTATISTICIAN: 
Bingshu Chen 
 
 
QUALITY OF LIFE COORDINATOR: 
Julie Lemieux 
 
 
CORRELATIVE SCIENCES CHAIR: 
John Bartlett 
 
 
STUDY COORDINATOR: 
Chad Winch 
 
 
REGULATORY SPONSOR: 
CCTG 
 
 
SUPPORTED BY: 
Pfizer 
 
(For contact information of study personnel see Final Page.) 
 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
i 
CONFIDENTIAL 
TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .................................................................................. 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 3 
 
1.0 
OBJECTIVES ......................................................................................................................................... 4 
1.1 
Primary Objective ................................................................................................................................... 4 
1.2 
Secondary Objectives .............................................................................................................................. 4 
1.3 
Tertiary/Exploratory Objectives .............................................................................................................. 4 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 5 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION.......................................................................... 10 
3.1 
Palbociclib ............................................................................................................................................. 10 
3.2 
Endocrine Therapy ................................................................................................................................ 15 
 
4.0 
TRIAL DESIGN ................................................................................................................................... 16 
4.1 
Stratification .......................................................................................................................................... 16 
4.2 
Randomization ...................................................................................................................................... 16 
 
5.0 
STUDY POPULATION ....................................................................................................................... 17 
5.1 
Eligibility Criteria ................................................................................................................................. 17 
5.2 
Ineligibility Criteria ............................................................................................................................... 19 
 
6.0 
PRE-TREATMENT EVALUATION ................................................................................................... 20 
 
7.0 
ENTRY/RANDOMIZATION PROCEDURES .................................................................................... 21 
7.1 
Entry Procedures ................................................................................................................................... 21 
7.2 
Stratification .......................................................................................................................................... 21 
7.3 
Randomization ...................................................................................................................................... 21 
 
8.0 
TREATMENT PLAN ........................................................................................................................... 23 
8.1 
Treatment Plan ...................................................................................................................................... 23 
8.2  
Palbociclib ............................................................................................................................................. 23 
8.3 
Endocrine Therapy ................................................................................................................................ 28 
8.4 
Concomitant Therapy ............................................................................................................................ 28 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT .............................................. 30 
9.1 
Evaluation During Protocol Treatment ................................................................................................. 30 
9.2 
Evaluation After Protocol Treatment .................................................................................................... 31 
 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 33 
10.1 
Definitions ............................................................................................................................................. 33 
10.2 
Response and Evaluation Endpoints ..................................................................................................... 33 
10.3 
Response Duration ................................................................................................................................ 35 
10.4 
Stable Disease Duration ........................................................................................................................ 35 
10.5 
Methods of Measurement ...................................................................................................................... 36 
 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
ii 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
11.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 37 
11.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 37 
11.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 37 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting............................ 38 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 39 
11.5 
CCTG Reporting Responsibility to Pfizer ............................................................................................. 40 
11.6 
Pfizer Reporting Responsibilities .......................................................................................................... 40 
11.7 
Reporting Safety Reports to Investigators ............................................................................................. 40 
 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 41 
12.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 41 
12.2 
Duration of Protocol Treatment ............................................................................................................ 41 
12.3 
Therapy After Protocol Treatment is Stopped ...................................................................................... 41 
12.4 
Follow-up Off Protocol Treatment ........................................................................................................ 41 
 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ............................................... 42 
13.1 
Central Pathology Review ..................................................................................................................... 42 
13.2 
Tissue Collection ................................................................................................................................... 42 
13.3 
Blood Collection ................................................................................................................................... 43 
 
14.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 44 
14.1 
Objectives and Design ........................................................................................................................... 44 
14.2 
Primary Endpoints and Analysis ........................................................................................................... 44 
14.3 
Sample Size and Duration of Study ...................................................................................................... 44 
14.4 
Safety Monitoring ................................................................................................................................. 45 
14.5 
Interim Analysis .................................................................................................................................... 45 
14.6. 
Quality of Life Analyses ....................................................................................................................... 45 
 
15.0 
PUBLICATION POLICY ..................................................................................................................... 46 
15.1 
Authorship of Papers, Meeting Abstracts, Etc ...................................................................................... 46 
15.2 
Responsibility for Publication ............................................................................................................... 46 
15.3 
Submission of Material for Presentation or Publication ........................................................................ 46 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 47 
16.1 
Regulatory Considerations .................................................................................................................... 47 
16.2 
Inclusivity in Research .......................................................................................................................... 47 
16.3 
Obtaining Informed Consent ................................................................................................................. 48 
16.4 
Discontinuation of the Trial .................................................................................................................. 49 
16.5 
Retention of Patient Records and Study Files ....................................................................................... 49 
16.6 
Centre Performance Monitoring ............................................................................................................ 49 
16.7 
On-Site Monitoring/Auditing ................................................................................................................ 50 
16.8 
Case Report Forms ................................................................................................................................ 50 
 
17.0 
REFERENCES ...................................................................................................................................... 51 
 
APPENDIX I -  
PATIENT EVALUATION FLOW SHEET ....................................................................... 53 
APPENDIX II -  
PERFORMANCE STATUS SCALES/SCORES .............................................................. 55 
APPENDIX III -  
DRUG DISTRIBUTION, SUPPLY AND CONTROL...................................................... 56 
APPENDIX IV -  
DOCUMENTATION FOR STUDY .................................................................................. 57 
APPENDIX V -  
NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .................... 58 
APPENDIX VI -  
QUALITY OF LIFE ASSESSMENT ................................................................................ 59 
APPENDIX VII -  THE TNM CLASSIFICATION OF MALIGNANT TUMOURS ..................................... 68 
APPENDIX VIII -  PROHIBITED MEDICATIONS ........................................................................................ 69 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
1 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG and Pfizer.  
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG and Pfizer to study 
personnel under my supervision. I will discuss this material with them to ensure that they are fully informed 
about the investigational product and the study.  
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of Pfizer and CCTG. The foregoing shall not apply to disclosure 
required by governmental regulations or laws; however, I will give prompt notice to Pfizer and CCTG of 
any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG or Pfizer with or without cause. 
 
I understand that Pfizer requires, as a condition of providing its product, Palbociclib (the “Pfizer Product”) 
for this study, the following license and option with respect to any invention or discovery, whether 
patentable or not, made by an investigator that results from the conduct of the Study and that encompasses 
treatment with, or the delivery, combination, manufacture, form, formulation, or the use of, the Pfizer 
Product (including use in combination with other products or agents), or that is or relates to a biomarker 
useful in selecting patients for treatment with the Pfizer Product (a Product-Related Invention”): 
 
1. A grant to Pfizer of a fully paid, perpetual, worldwide, non-exclusive, royalty-free license for all 
purposes to each Product-Related Invention owned by an investigator. Such non-exclusive license to 
Pfizer will include the rights to (1) sublicense to Pfizer affiliates, contractors, or collaborators working 
for benefit of Pfizer or in connection with a Pfizer, Pfizer affiliate, or collaboration product or services, 
and (2) sublicense or assign to a successor in interest or to some or all rights in a Pfizer product to 
which the Product-Related Invention is relevant. 
 
2. A grant to Pfizer of an option to obtain an exclusive worldwide license for all purposes, with full rights 
to sublicense and assign, to each Product-Related Invention owned in a whole or in part by an 
investigator, under terms to be negotiated in good faith between Pfizer and the investigator. 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
2 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
I agree as an investigator to grant the above described non-exclusive license and option to Pfizer as required.  
 
I agree to use the Pfizer Product only as specified in the protocol. If I use, or permit others to use, the Pfizer 
Product for any research not authorized by the protocol (“Unauthorized Research”) I acknowledge that 
Pfizer will be the exclusive owner of the result of that research, including any inventions or discoveries that 
arise out of it, whether patentable or not (collectively the “Unauthorized Inventions”) and I will assign to 
Pfizer all interest in such Unauthorized Inventions and will cooperate with Pfizer to ensure execution and 
delivery of all documentation that Pfizer reasonably deems necessary to perfect Pfizer’s rights in the 
Unauthorized Inventions. 
 
I understand that any inventions or discoveries that are not a Product-Related Invention and/or 
Unauthorized Inventions will be owned by the inventors. For any inventions or discoveries that may be 
jointly made by CCTG, investigator and/or Pfizer, the inventions or discoveries will be jointly owned and 
each joint owner will retain its right to practice and exploit its undivided interested in any such invention 
or discovery without the consent of and without accounting to its co-owners.  
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
Pfizer and CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
___________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG MA.38 
 
CENTRE: ___________________________________________ 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
3 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
TREATMENT SCHEMA 
 
Population 
 
Women with documented evidence of estrogen receptor positive, HER2 negative, advanced/metastatic 
breast cancer, after failure of prior endocrine therapy  
 
Stratification 
• 
Centre 
• 
Visceral metastases: yes versus no 
• 
Duration of exposure to most recent endocrine therapy prior to randomization: ≥ 6 months versus < 6 
months in the advanced/metastatic setting or ≥ 24 months versus < 24 months in adjuvant setting 
• 
Planned use of Fulvestrant versus Tamoxifen versus Aromatase Inhibitor (AI) 
 
 Advanced Breast Cancer 
 ER+, HER2- 
 Second Line Endocrine Setting 
 Informed Consent 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
1:1 
 
ARM 1: 
Palbociclib 100 mg po daily  
+  
Fulvestrant or Tamoxifen or AI at the standard 
doses/schedules  
 
 
 ARM 2: 
Palbociclib 125 mg po daily 3 out of 4 weeks 
+  
Fulvestrant or Tamoxifen or AI at the standard 
doses/schedules 
Planned sample size: 180 
 
Endpoints 
 
Primary: 
• 
Progression Free Survival  
 
Secondary: 
• 
Safety and Tolerability 
• 
Response Rate (in patients with measurable disease) 
• 
Duration of Response 
• 
Clinical Benefit Rate 
• 
Overall Survival 
 
Tertiary/Exploratory: 
• 
Patient Reported Quality of Life using EORTC QLQ-C30 and trial specific checklist 
• 
Predictive biomarker assessment from tissue and blood sample collection 
• 
A biorepository of tissues for future correlative studies  


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
4 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To compare the progression-free survival of two different dose regimens of palbociclib in 
combination with endocrine therapy (fulvestrant or tamoxifen or AI) as second line therapy in 
women with ER positive, HER2 negative, advanced/metastatic breast cancer 
 
1.2 
Secondary Objectives 
 
To evaluate and compare between the two treatment arms with respect to:  
• 
Safety and Tolerability 
• 
Response Rate (in patients with measurable disease) 
• 
Duration of Response 
• 
Clinical Benefit Rate 
• 
Overall Survival 
 
1.3 
Tertiary/Exploratory Objectives 
 
To explore: 
• 
Patient Reported Quality of Life using EORTC QLQ-C30 and trial specific checklist 
• 
Predictive biomarker assessment from tissue and blood sample collection 
• 
A biorepository of tissues for future correlative studies 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
5 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Although reliable identification of steroid receptors and the introduction of tamoxifen and 
aromatase inhibitors resulted in major improvements in outcomes for patients with breast cancer, 
many patients will eventually relapse or progress due to the development of resistance to endocrine 
therapy. In the advanced disease setting, occurrence of resistance results in lower response rates 
and shorter durations of progression free survival (PFS) with every further line of palliative 
endocrine therapy [Bergh 2012; Chia 2008; Howell, 2002]. Resistance may be attributed to a shift from 
estrogen-dependent tumour growth to the activation of alternate growth factor signaling pathways 
and growth signal activation despite the absence of estrogen. 
 
Cell cycle progression from G1 to S phase requires a complex of cyclin-dependent kinase (CDK) 
4 and 6 (CDK6) and D cyclins (CCND1-3) to phosphorylate retinoblastoma (Rb). In malignant 
cells, genetic changes, including CCND1 amplification common in breast cancer, can result in loss 
of controlled cell cycle progression through G1, rendering CDK4/6 inhibition an attractive 
biological approach [Osbourne 2005]. Palbociclib is an orally available CDK inhibitor with potential 
antineoplastic activity. Palbociclib selectively inhibits CDK4 and CDK6 inhibiting Rb protein 
phosphorylation early in the G1 phase leading to cell cycle arrest [Caldon2006; Dean 2012; Finn 2009]. 
This suppresses DNA replication and decreases tumour cell proliferation. 
 
Clinical trials of palbociclib have shown impressive clinical activity without undue toxicity. Phase 
I data testing a 3 weekly out of 4 dosing schedule (dose range (25-150 mg daily) identified 125 mg 
as the recommended phase two dose (RPTD) [Flaherty 2012]. Uncomplicated grade 3 or 4 
neutropenia was the dose limiting toxicity (DLT). Pivotal phase II data from Finn et al 
(PALOMA 1) was derived from a study comparing palbociclib 125 mg orally daily 3 out of 4 weeks 
plus daily letrozole 2.5 mg to single agent letrozole [Finn 2014]. The primary endpoint was PFS. 
Two cohorts were enrolled based on biomarker status [ER+, HER2– (cohort 1) and ER +, HER2- 
plus amplification of cyclin D1, loss of p16 or both (cohort 2)]. An unplanned interim analysis of 
cohort 1 led to closure of cohort 2 and combination of both cohorts for the PFS analysis. Median 
PFS for the combined group was 10.2 months for the letrozole arm compared to 20.2 months for 
the combined arm (HR 0.488 95% CI 0.319-0.748; one sided p=0.0004). Grade 3/4 neutropenia 
was seen in 54% of 83 patients enrolled in the combined arm versus 1% Of 77 in the letrozole 
group. No cases of febrile neutropenia or neutropenia related infections were reported in the study. 
Based on these results, the US FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer, 
Inc.) on February 3, 2015 for use in combination with letrozole for the treatment of postmenopausal 
women with ER+, HER2-, advanced breast cancer as initial endocrine-based therapy for their 
metastatic disease. Mature results for efficacy and toxicity were presented at the 2017 American 
Society of Clinical Oncology Annual Meeting. Median PFS was improved in all subgroups in the 
combination treatment arm compared to letrozole. Adverse events were manageable including in 
those patients with visceral disease. As of December 2016, there were 116 OS events. Median OS 
was 37.5 mos (95% CI: 31.4, 47.8) with P+L vs 34.5 mos (95% CI: 27.4, 42.6) for L (HR = 0.897 
[95% CI: 0.623, 1.294]; p= 0.281) 
 
The efficacy of palbociclib plus letrozole was confirmed in the phase III setting (PALOMA 2) [Finn 
2016]. Combination therapy improved PFS compared to letrozole: HR for progression or death, 
0.58; 95% CI, 0.46 to 0.72; P<0.001. The median PFS for the palbociclib plus letrozole treated 
group was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) versus 14.5 months 
(95% CI, 12.9 to 17.1) in the letrozole treated group. Adverse events were anticipated based on 
previous clinical data. The most common grade 3 or 4 adverse events were neutropenia (occurring 
in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), 
leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). 


 
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ADMIN UPDATE #1: 2017-JUL-05 
The phase III PALOMA-3 study compared fulvestrant plus palbociclib versus fulvestrant plus 
placebo [Turner 2015]. A preplanned interim analysis demonstrated a significantly longer PFS 
(primary endpoint) favoring the combination arm: investigator assessed median PFS 9.2 months 
versus 3.8 months HR 0.42, 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse 
events (regardless of causality) were hematological and more frequent in the palbociclib plus 
fulvestrant arm versus fulvestrant arm alone including: leukopenia (25.5% versus 0.6%), 
neutropenia (62.0%, vs. 0.65), anemia (2.6% vs. 1.7%) and thrombocytopenia (2.3% vs. 0%). 
Notably, the incidence of febrile neutropenia was the same (0.6%) in both arms although there were 
numerically more infections in the combination arm, mostly low grade (34.2 versus 24.4%). Dose 
reductions occurred in more patients treated with palbociclib (31.6%) than with placebo (1.7%). 
Rates of discontinuation due to adverse events were numerically low in both arms but higher in 
patients receiving palbociclib (2.6% compared to 1.7% respectively). Subset analysis showed 
comparable benefit in premenopausal versus postmenopausal women (P = 0.94 for interaction 
between drug assignment and menopausal status). The final analysis was recently reported 
[Cristofanilli 2016]. The HR for progression free survival was o.46 (95% CI 0.36-0.59, p< 0.001). 
Biomarker analyses failed to demonstrate predictive roles for PIK3A status or hormone receptor 
expression level on response. Overall survival data is in progress. An in depth safety analysis was 
performed [Verma 2016], No new safety signals were seen and the rate of febrile neutropenia with 
palbociclib expsosure was < 1%. Palbociclib associated neutropenia was effectively managed by 
dose reductions or delays and without any apparent impact on disease outcome. 
 
There is accumulating experience with combination therapy palbociclib and tamoxifen. The effect 
of multiple dosing of tamoxifen (60 mg QD for 4 days followed by 20 mg QD for 23 days), on the 
single-dose PK of palbociclib (125 mg), was evaluated in 25 healthy fasted subjects in Study 
A5481026. Administration of palbociclib in the presence of tamoxifen and its metabolites (4-
hydroxy-tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-N-desmethyl-tamoxifen) at steady 
state showed that palbociclib exposure was comparable with that when palbociclib was given alone. 
The ratios (90% CIs) of the adjusted geometric means of palbociclib AUCinf and Cmax were 108% 
(104%-111%) and 116% (105%-129%), respectively, following administration of palbociclib with 
multiple doses of tamoxifen relative to palbociclib administered alone. These results indicate that 
it is not necessary to adjust palbociclib starting dose when co-administering with tamoxifen. Studies 
are ongoing evaluating the efficacy of this combination (NCT01864746, NCT02513394).  
 
Cumulative clinical data suggest that a significant number of patients treated with palbociclib 
experience dose interruptions and delays due to neutropenia without any apparent increase in febrile 
neutropenia compared to placebo. In addition, preclinical studies suggest that palbociclib exerts an 
antiproliferative effect on cancer cells that is released when the drug is discontinued Palbociclib 
Investigator Brochure 2015. These data suggest that a better therapeutic index may be obtained by 
maintaining continuous exposure using a lower but still biologically relevant dose of palbociclib. 
Simulated trough and absolute neutrophil profiles based on actual and modelled data indicate that 
a 100 mg continuous daily dose will be associated with an ANC > 1000 and greater systemic 
exposure to drug compared with the FDA approved dosing schedule of 125 mg for 3 out of 4 weeks.  
 
This study is designed to provide data regarding the optimal scheduling of palbociclib by 
comparing the FDA approved schedule of 125 mg daily for 21 out of 28 days to a continuous dosing 
schedule of 100 mg daily. In addition to evaluating antitumour activity, the safety, tolerability and 
impact on QOL of the two regimens will be assessed. A specimen biobank will also be compiled 
using tissue collected on study (see suggestions for future biomarkers studies below).  


 
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ADMIN UPDATE #1: 2017-JUL-05 
Quality of Life  
 
Given the incurable nature of advanced breast cancer and the high incidence of treatment related 
adverse events associated with therapy, patient reported quality of life (QOL) data provide an 
important perspective on the impact of an intervention, above and beyond treatment induced 
changes in lifespan. This is especially true for the current proposal which evaluates two different 
schedules of administration of the same combination of drugs which may have modest differences 
in disease control but important differences in adverse event and QOL experiences. Further 
justification of measurement of QOL is provided by previous research demonstrating that QOL 
data provides additional information to systematically collected adverse event data [Huschka 2007; 
Paul 1991].  
 
The initial studies evaluating palbociclib did not evaluate QOL in a robust manner. In the trial by 
Finn et al (2014), QOL was not measured but adverse events were numerically higher in the 
palbociclib containing arm (including fatigue, arthralgia, alopecia, diarrhea, hot flushes, decreased 
appetite, dyspnea, vomiting, bone pain, stomatitis, and peripheral neuropathy). Quality of life was 
collected but not reported in the primary publication of the PALOMA 1 study. 
 
The recently reported phase III trial comparing palbociclib to placebo in combination with 
fulvestrant in the second line setting measured QOL using the EORTC QLQ C30 and BR23 
instruments. Global QOL measurements favoured the palbociclib arm, as did improvement in 
baseline pain [Harbeck 2016]. More data is required to inform the patient perspective on treatment 
with palbociclib. 
 
In the current study QOL will be collected at predetermined time points during administration of 
protocol therapy as well as at the time of discontinuation of therapy due to adverse events or 
progression of disease. 
 
Two instruments will be used to capture the QOL experience of patients, the EORTC QLQ-C30 
and a trial specific checklist. The EORTC QLQ-C30 will be used to capture the multidimensionality 
of QOL in metastatic breast cancer. The EORTC QLQ-C30 is a widely used, cancer specific health-
related QOL questionnaire which is well accepted by patients [Aaronson 1993; Conroy 2004]. It contains 
five functional subscales (physical, role, cognitive, emotional, social), three multi-item symptom 
subscales (fatigue, pain and nausea), six single items (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea, financial impact) and a global health measure (physical condition and global 
QOL). The questionnaire uses 4 and 7-point scales. For each subscale, the range of possible scores 
is between 0 and 100. Convergent and criterion validity has been demonstrated for this 
questionnaire in metastatic breast cancer [Bottomlay 2004; Mclachlan 1998] and reliability is adequate 
[Aaronson 1993; Hjermstad 1995]. The EORTC QLQ-C30 has been shown to be responsive to change 
associated with chemotherapy and with disease progression [Osoba 1998; Lemieux 2007]. The 
questionnaire is available in multiple languages. A trial specific checklist will be added because 
there are no questions in the EORTC QLQ-C30 regarding mucositis and peripheral neuropathy. 
The trial specific checklist items were selected following a search of the CCTG QOL data bank 
and items currently in use in other trials. Completion of the trial specific checklist will be mandatory 
for all patients. Translations will be provided as necessary. The same scale as used in the EORTC 
QLQ-C30 will be used.  


 
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Correlative Biological Studies 
 
Predictive biomarkers for response to palbociclib are lacking. To date, preclinical and clinical data 
have identified only estrogen receptor status as a predictive biomarker [Finn 2014; Jiang 2014]. Data 
from the pivotal phase II and III studies in advanced disease show that not all patients with estrogen 
receptor positive disease will respond to palbociclib and those who respond initially will develop 
resistant/progressive disease over time [Finn 2014; Turner 2015].  
 
A key correlative study goal will be to survey genomic alterations implicated in G1/S checkpoints. 
Planned studies on the tumour tissue include CDK2,4,6 mutations status and CNV analysis for 
CDK2, 4, 6, CCND1-3, CCNE1,2, Rb and p16 using the comprehensive Oncomine panel 
(Thermofisher). This will form the first clinical comprehensive profiling of the G1/S checkpoint 
regulators. Exploratory analysis of key genomic alterations may be extended to circulating tumour 
DNA based on these results. 
 
To address the important unanswered questions regarding identification of biomarkers predictive 
of response and resistance to palbociclib, a robust and comprehensive biorepository will be 
assembled as part of this study conduct. Details of the correlative study requirements can be located 
in section 13.0 of the protocol.  
 
Tumour Collection: 
Mandatory archival tissue will be collected from the most recent pathological tumour specimen. 
This includes metastatic tumour, if available, or from primary tumour resection at first diagnosis 
of breast cancer.  
 
Tumour specimens will be collected at the time of progression on study for all patients when 
feasible.  
 
Collection of sequencing samples (cell free DNA, lymphocytes, whole blood and serum/plasma): 
 
Analysis of circulating cell free (tumour) DNA, focusing initially on mutations/alterations in 
CDK4/6 signaling pathways, will allow researchers to identify key mutations. Over time, these 
mutations can be used to track the emergence of resistant subclones within patients tumours. With 
deep sequencing (1500 fold coverage or greater) now possible for known mutations (identified in 
the pre-treatment biopsies), we will be able to assess the impact of drug treatment on separate clones 
within the tumour. Circulating markers in serum/plasma have also been shown to provide measures 
of cell death during treatment phases. Collectively these samples will allow exploration of the 
mechanisms underlying the emergence of treatment resistance. 
 
Cell-Free DNA and Lymphocyte Collection:  
Cell-Free DNA will be collected at baseline and pre-specified time points for exploratory analyses 
to identify predictive biomarkers of response and resistance to protocol therapy and to examine 
temporal qualitative and quantitative changes in tumour DNA over time.  
 
Blood lymphocytes will be collected at baseline for studies of pharmacogenomics/ genetic 
predictors of toxicity and response to protocol therapy. 
 
Collection of Serum and Plasma: 
Serum and plasma will be collected at baseline and pre-specified time points for exploratory 
analyses to identify predictive biomarkers of response and resistance to protocol therapy and to 
examine temporal qualitative and quantitative changes in proteomic markers over time.  


 
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Studies evaluating the impact of the altered dosing schedule on target modulation (RB) in 
tumour or surrogate tissue are planned pending clarification of methodology. The protocol 
documents will be modified to incorporate these additions as appropriate.  
 
Summary 
 
In summary, this study will address the hypothesis that the combination of endocrine based 
anticancer therapy and palbociclib at a dose of 100 mg po daily will result in greater antitumour 
efficacy due to a greater systemic exposure and fewer dose interruptions of drug compared to the 
current FDA approved dose and schedule of palbociclib. Importantly, the altered treatment 
schedule may be associated with a better safety profile including fewer instances of grade 4 
neutropenia and febrile neutropenia. 
 
The current proposal will further the scientific and clinical understanding of hormone receptor 
positive breast cancer treated with palbociclib via the collection of efficacy, quality of life, safety 
and adverse event data and by the compilation of a comprehensive biorepository of tissues for 
future correlative biology studies.  
 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Palbociclib 
 
3.1.1  Name and Chemical Information 
 
The information provided is in support of PD-0332991-00 (freebase). See the current Palbociclib 
Investigator Brochure for the most up to date information. PD-0332991-00 capsules will be 
provided as the active ingredient with precedented excipients filled in hard gelatin capsules 
composed of gelatin and precedented colorants. 
 
3.1.2 
Chemical Structure 
 
 
 
Molecular Formula: C24H29N7O2 
Molecular Weight: 447.54 daltons 
 
3.1.3 
Mechanism of Action 
 
Palbociclib, an orally active pyridopyrimidine, is a potent and highly selective reversible inhibitor 
of cyclin-dependent kinase (CDK) 4 and CDK6. The compound prevents cellular DNA synthesis 
by prohibiting progression of the cell cycle from G1 into the S phase. Specifically, Palbociclib 
inhibits CDK4/6-catalyzed phosphorylation of the retinoblastoma protein (Rb), which is required 
for cell division.  
 
Palbociclib has selectivity for CDK4/6, with little or no activity against a large panel of 274 other 
protein kinases including other CDKs and a wide variety of tyrosine and serine/threonine kinases. 


 
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3.1.4 
Experimental Antitumour Activity 
 
In human tumour cell lines palbociclib has been shown to have anti-proliferative effects by 
inhibiting thymidine incorporation into the DNA of a panel of Rb-positive human breast, colon and 
lung carcinoma cell lines. Additionally, palbociclib has been shown to be effective in preventing 
cell cycle progression in human leukemias and in nontransformed human epithelial cells and 
fibroblasts and is equally effective in suppressing cell division in human tumour cell lines (breast 
and colon). In one model, Colo-205, doses as low as 12.5 mg/kg caused a 13-day growth delay, 
indicating a 90% inhibition of tumour growth rate. MDA-MB-453 breast carcinoma cells that were 
exposed to various concentrations of palbociclib for 24 hours show a significant increase in the 
percentage of cells in the G1 phase of cell division with a concomitant decline in other phases of 
the cell cycle. To provide further evidence of the selectivity of palbociclib, the compound was 
tested against Rb-negative tumour cells, which should not be sensitive to a specific CDK4/6 
inhibitor. Palbociclib was tested against the MDA-MB-468 human breast carcinoma and the DU-
145 prostate tumour models, both of which are Rb-negative. Palbociclib had no anti-proliferative 
activity on these cells. Thus, evidence indicates that palbociclib induces anti-tumour activity due 
to the inhibition of CDK4/CDK6 protein kinase activity. 
 
Further studies investigated whether continuous daily dosing of palbociclib was needed for optimal 
efficacy. Four dosing schedules were employed against the MDA-MB-435 breast carcinoma model 
over 14 days of treatment, including continuous daily, every other day, every third day, and 3 
courses of 3 days dosing followed by 4-day drug holidays. The design of this experiment was such 
that the total compound administered over the 2-week period was identical for each treatment 
schedule. The results show that a similar degree of efficacy was attained with all schedules, 
implying that an intermittent regimen is feasible without compromising activity. Similar 
experiments were conducted against the Colo-205 colon carcinoma model. Again, intermittent 
schedules were as efficacious as daily dosing, with tumour regressions occurring during all dosing 
regimens. 
 
In parallel with the in vivo efficacy tests, tumours were harvested for pharmacodynamics analysis 
to ensure that anti-tumour activity correlated with modulation of the target and to provide 
confidence that the proposed biomarker would predict for efficacy. Efficacious and non-efficacious 
doses of palbociclib were given to mice bearing the MDA-MB-435 breast carcinoma and the 
phosphorylation status of serine-780 on Rb in tumour tissue was monitored over time. The results 
show that while all doses caused a reduction in the biomarker shortly after drug administration, 
phosphorylation returned at the non-efficacious doses (12.5 and 37.5 mg/kg) over the 24-hour 
interval before the next dose. However, the highly efficacious dose of 150 mg/kg suppressed Rb 
serine-780 phosphorylation during the full 24-hour period. These data suggest that complete 
suppression of Rb phosphorylation needs to be maintained between drug doses to achieve 
significant efficacy against this particular tumour model. Because the lower doses result in transient 
target modulation, more frequent dosing at these doses might result in improved efficacy by 
maintaining suppression of phosphorylation. Similar experiments with the Colo-205 colon 
carcinoma xenografts, which are exquisitely sensitive to palbociclib, shows that complete 
suppression of Rb phosphorylation between doses was found to be unnecessary for producing 
growth inhibition. However, for maximal effects against Colo-205 tumours (i.e. regression), total 
inhibition had to be maintained. 


 
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3.1.5 
Animal Toxicology 
 
Palbociclib was administered to rats and dogs in toxicity studies up to 39 weeks in duration, with a 
dosing regimen of 3 weeks of dosing followed by a 1-week non-dosing period. The no observed 
adverse effect levels (NOAELs) in the 27-week and 39-week toxicity studies were at <10 (males) 
and <50 (females) mg/kg/day in the rat and <0.2 (males) and 3.0 (females) mg/kg/day in the dog. 
Systemic exposure (AUC24) associated with the 10 and 50 mg/kg/day doses in male and female 
rats were 6000 and 2650 ng•h/mL, respectively, and with the 0.2 and 3.0 mg/kg/day doses in male 
and female dogs were 96.6 ng•h/mL and 2050 ng•h/mL, respectively. The primary toxicities 
identified from these studies included hematolymphopoietic effects; altered glucose metabolism 
and related effects on the pancreas, eye, teeth, kidney, and adipose tissue; and effects on bone, male 
reproductive organs, and embryofetal development. Other palbociclib-related findings were in 
gastrointestinal tissue, appeared as vacuolation in multiple tissues, and included effects on the liver, 
kidney, adrenal gland, and respiratory system, and prolonged coagulation time that were of limited 
severity and/or lacked degenerative features. Dose-related decreases in body weight and/or food 
consumption were observed following single and repeat dosing, and moribundity preceded by 
clinical signs of intolerance was observed at ≥100 mg/kg/day in rats and ≥ 10 mg/kg/day in dogs 
at doses where systemic unbound AUC24 exposures (≥ 3663 ng•h/mL and ≥ 10119 ng•h/mL, 
respectively) exceeded those considered clinically relevant. In genetic toxicity tests, palbociclib 
was identified as an aneugen, with a NOAEL for micronuclei formation at 50 mg/kg/day (unbound 
Cmax 225 ng/mL and AUC24 of 2163 ng•h/mL). 
 
3.1.6 
Clinical Trials 
 
A total of 400 healthy volunteers have received single doses of palbociclib, ranging from 50 mg to 
150 mg as of the December 10, 2014 data cut off of the February 2015 Investigator Brochure. The 
most frequently reported treatment-emergent adverse events (TEAEs) of any grade, regardless of 
causality were nausea, headache, diarrhea, abdominal distention, dizziness, somnolence, abdominal 
discomfort, fatigue and back pain. The most frequently reported TEAEs of any grade, considered 
related to study treatment were headache, nausea, somnolence and abdominal distention. In the 
healthy volunteer studies abnormal laboratory values were not necessarily considered adverse 
events, however, neutropenia and lymphocytopenia were frequently observed (14.5% and 11.5% 
of patients, respectively).  
 
Palbociclib has been administered to over 281 subjects with cancer in both monotherapy and 
combination therapy regimens in phase I-III clinical trials at doses up to 225 mg. The most 
frequently reported TEAEs (≥ 20% of patients) of any grade (regardless of causality) for 
palbociclib administered as a single agent are neutropenia, thrombocytopenia, anemia, fatigue, 
constipation, nausea, decreased appetite, vomiting and diarrhea. In all clinical studies, neutropenia 
has been among the most frequently associated adverse event.  
 
Please refer to the most recent version of the Investigator Brochure for the detailed risk profile. 


 
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3.1.7 
Pharmacokinetic Studies 
 
As of December 10, 2014, twenty-one clinical studies have evaluated the PK of palbociclib. Four 
of these trials were conducted in patients with advanced malignant disease. Seventeen phase I 
clinical pharmacology and biopharmaceutic studies of palbociclib were conducted in healthy 
subjects. Ten of these 17 clinical trials were clinical pharmacology studies conducted to investigate 
the absorption, distribution, metabolism, and excretion of palbociclib as well as examine the 
potential for DDI with palbociclib. The remaining 7 of the 17 clinical trials were biopharmaceutic 
studies conducted to examine the bioavailability, bioequivalence, and food effect of the palbociclib 
formulations.  
 
Pharmacokinetic (PK) data from patients with advanced cancer from Study A5481001 indicate that 
the plasma pharmacokinetics of palbociclib are low to moderately variable with generally dose 
proportional exposures over the dose range evaluated (25 mg to 225 mg) following single and 
multiple doses. PK data from Studies A5481001, A5481003, and A5481010 indicate that 
palbociclib is slowly absorbed with a median time of maximum concentration (Tmax) between 4 and 
8 hours post-dose, and is slowly eliminated with an elimination half-life (t1/2) ranging from 23.2 
hours to 28.8 hours. Palbociclib accumulates after repeated daily dosing (median Rac ranged from 
1.9 to 2.4), which was consistent with its terminal t1/2. In Study A5481010, the median Rss (the 
predicted accumulation to estimate linearity) was 1.1, indicating that palbociclib clearance does not 
change over time. In Study A5481003, palbociclib was shown to achieve steady-state 
concentrations following 8 days of QD dosing. The palbociclib geometric mean volume of 
distribution (Vz/F) was 2583 L in women with advanced breast cancer (Study A5481003), which 
is significantly greater than total body water (42 L), indicating that palbociclib extensively 
distributes to peripheral tissues. 
 
In humans, metabolism is the major route of elimination of palbociclib. Following a single oral 
administration of [14C]palbociclib to healthy subjects (Study A5481011), the overall median 
recovery of the administered radioactivity in the excreta was 91.6% with a median of 17.5% 
recovered in urine and a median of 74.1% recovered in feces. Excretion of unchanged palbociclib 
in the feces and urine was 2.3% and 6.9% of dose, respectively, indicating that excretion plays a 
minor role in elimination of palbociclib. A study in healthy volunteers (A5481015) indicated that 
the absolute oral bioavailability of palbociclib was approximately 46%.  
 
In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the 
metabolism of palbociclib. Palbociclib is a weak time-dependent inhibitor of CYP3A following 
daily 125 mg dosing to steady state in humans. Data from studies involving co administration of 
palbociclib with strong CYP3A inducers and inhibitors demonstrate important changes in the PK 
of palbociclib and thus concurrent administration of these types of drugs with palbociclib should 
be avoided (studies A5481016, A5481017). 
 
Food exposure affects the PK of palbociclib by increasing the AUC inf and C Max by 12-38% 
depending on fat content when food is given 1 hour before and or 2 hours after palbociclib 
administration (A5481021). In addition, food intake significantly reduces the intersubject and 
intrasubject variability of palbociclib exposure. Based on these results, palbociclib commercial free 
base capsules should be taken with food. 
 
The co-administration of drugs that alter the gastric pH such as proton pump inhibitors, local 
antacids or H2 receptor antagonists does not meaningfully impact palbociclib exposure when 
palbociclib is taken with food (study A5481038).  


 
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Data from a DDI study in healthy male subjects indicated that palbociclib exposures were 
comparable when a single dose of palbociclib was co-administered with multiple doses of 
tamoxifen and when IBRANCE was given alone. 
 
Mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1.0 to 
1.5 x ULN and any AST), has no effect on the exposure of palbociclib. The pharmacokinetics of 
palbociclib have not been studied in patients with moderate or severe hepatic impairment (total 
bilirubin >1.5 × ULN and any AST). 
 
Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had 
mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal 
impairment (30 mL/min ≤ CrCl < 60 mL/min). Palbociclib exposure in not affected by mild or 
moderate renal impairment (30 mL/min ≤ CrCl). The pharmacokinetics of palbociclib have not 
been studied in patients with severe renal impairment. 
 
A pharmacokinetic/pharmacodynamic analysis to evaluate the relationship between palbociclib 
exposure and ECG endpoints (RR and QTc intervals) were developed using pooled data from 3 
clinical trials in patients with advanced malignant disease (Studies A5481001, A5481002, and 
A5481003). The study population consisted of 48 men and 136 women with a median (range) body 
weight of 73.0 (37.9-123) kg and age of 61.5 (22-89) years old. Palbociclib doses ranged from 25 
mg to 225 mg QD. The data collected from 184 patients consisted of 569 ECG-palbociclib 
concentration-matched pairs; the observed plasma concentrations had a median (range) of 55.2 
(2.51-329) ng/mL. The average heart rate, RR, QT, QT corrected for heart rate according to Bazett 
(QTcB), QT corrected for heart rate according to Fridericia (QTcF), and QTcS (QT interval 
corrected for heart rate according to a study-specific correction factor) at baseline for 
ECG-palbociclib concentration matched data were 76.8 beats per minute, 808 msec, 380 msec, 
425 msec, 409 msec, and 412 msec, respectively. 
 
The results of the analysis indicate that palbociclib does not appear to have a concentration-
dependent effect on heart rate. A slight positive linear relationship between palbociclib 
concentration and QTcS was observed; however, at the mean or median steady-state palbociclib 
Cmax following administration of the recommended clinical dose of palbociclib (125 mg QD) in 
patients with cancer, the upper bound of the one-sided 95% CI for the increase in QTcS fell below 
the threshold of 10 msec, suggesting that QT prolongation is not a safety concern for palbociclib at 
the recommended clinical dose according to the criteria described in the ICH guidance for Industry 
E14. Similar results were obtained when QTcF and QTcB were used. 
 
3.1.8 
Pharmaceutical Data 
 
Supplied:  
Palbociclib is an oral capsule and will be supplied in three strengths: 75 mg, 100 mg, or 125 mg. 
 
Stability: 
The shelf life of Palbociclib will be indicated on the label 
 
Storage:  
Palbociclib must be stored at room temperature (15ºC to 30ºC) 
 
Route of Administration:  
Orally 


 
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3.2 
Endocrine Therapy 
 
The following standard of care endocrine treatment agents are allowed for each treatment arm:  
• 
Tamoxifen  
• 
Non-steroidal aromatase-inhibitors (anastrozole, letrozole) 
• 
Steroidal aromatase inhibitor (exemestane)  
• 
Fulvestrant 
 
Ovarian suppressive therapy (LHRH agonists, surgical or radiologic ablation of the ovaries) is 
required for pre-menopausal women who will be treated on study with fulvestrant or an aromatase 
inhibitor and is optional for premenopausal women who will be treated on study with tamoxifen. 
 
All standard of care agents will be administered at the discretion of the principal investigator (or 
his/her designee) as well as according to standard institutional or regional practice.  
 
Administration of endocrine therapy is performed on an outpatient, self-administration basis 
according to local requirements and local standard practice. On days when patient is scheduled for 
a clinic visit, the patient should take scheduled endocrine therapy dose once all visit assessments 
have been performed (either at home or in the clinic) unless otherwise indicated.  
 


 
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ADMIN UPDATE #1: 2017-JUL-05 
4.0 
TRIAL DESIGN 
 
This is an open label multi-centre, multi-national randomized phase II trial of two different dose 
regimens of palbociclib in combination with fulvestrant or tamoxifen or AI in women with ER 
positive, HER2 negative advanced/metastatic breast cancer.  
 
4.1 
Stratification 
 
Patients will be stratified by: 
• 
Centre 
• 
Visceral metastases: yes vs. no 
• 
Duration of exposure to most recent endocrine therapy prior to randomization: ≥ 6 months 
versus < 6 months in the advanced/metastatic setting or ≥ 24 months versus < 24 months in 
adjuvant setting 
• 
Planned use of Fulvestrant versus Tamoxifen versus Aromatase Inhibitor 
 
4.2 
Randomization 
 
Patients will be randomized (1:1) to receive one of the following treatments, to a planned sample 
size of 180 patients.  
 
Patients will be randomized to one of the following two arms: 
Arm 
Agent(s) 
Dose 
Route 
Schedule 
Duration 
1 
Palbociclib 
100 mg  
PO 
Daily for 28 day cycle 
Treat until 
progressive 
disease 
Endocrine 
Therapy 
Fulvestrant* 500 mg 
IM 
Days 1 and 15 of cycle 1 and then 
on day 1 of each 28 day cycle 
 
OR 
 
Tamoxifen** 20 mg 
PO 
Daily for 28 day cycle 
 
OR 
 
Aromatase Inhibitor*: 
 
Letrozole 2.5 mg  
Anastrozole 1 mg 
Exemestane 25 mg 
PO  
Daily for 28 day cycle 
2 
Palbociclib 
125 mg  
PO 
Days 1-21 of each 28 day cycle 
Treat until 
progressive 
disease 
Endocrine 
Therapy 
Fulvestrant* 500 mg  
IM 
Days 1 and 15 of cycle 1 and then 
on day 1 of each 28 day cycle 
 
OR 
 
Tamoxifen** 20 mg 
PO 
Daily for 28 day cycle 
 
OR 
 
Aromatase Inhibitor*: 
 
Letrozole 2.5 mg  
Anastrozole 1 mg 
Exemestane 25 mg 
PO 
Daily for 28 day cycle 
* 
In premenopausal women ovarian suppression therapy is required 
** In premenopausal women ovarian suppression therapy is optional 


 
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5.0 
STUDY POPULATION 
 
Women with documented evidence of estrogen receptor positive HER2 negative breast cancer, 
which is recurrent or advanced/metastatic, who have received one previous line of prior endocrine 
therapy in the adjuvant or metastatic setting.  
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed prior to calling for randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfil all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Premenopausal and postmenopausal women 18 years of age or older.  
 
5.1.2 
Histologically confirmed adenocarcinoma of the breast, with ER positive and HER2 negative status 
based on local testing on most recent pathological tumour specimen.  
 
5.1.3 
Patients must satisfy the following criteria for prior therapy: 
• 
Progressed during treatment or within 12 months of completion of adjuvant endocrine therapy  
OR 
• 
Progressed during prior endocrine therapy for advanced/metastatic disease.  
 
Note: ‘Progressed during endocrine therapy’ means that the patient progressed while on or within 
1 month after discontinuation of endocrine therapy. 
 
5.1.4 
One line of chemotherapy for advanced/metastatic disease (regardless of prior adjuvant 
chemotherapy use) is allowed in addition to endocrine therapy. 
 
5.1.5 
Patients must have evidence of disease to be eligible for the study, but measurable disease is not 
mandatory.  
 
5.1.6 
For those patient with measureable disease who will be included in the response assessment, the 
following criteria must apply: 
• 
X-ray ≥ 20 mm  
• 
Spiral CT scan or physical exam ≥ 10 mm (lymph nodes must be ≥ 15 mm in the short axis) 
• 
Conventional CT scan, MRI ≥ 20 mm  
• 
Measurable lesions must be outside a previous radiotherapy field if they are the sole site of 
disease, unless disease progression has been documented. 


 
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ADMIN UPDATE #1: 2017-JUL-05 
Tumour lesions previously irradiated or subjected to other loco regional therapy will only be 
deemed measurable if progression at the treated site after completion of therapy is clearly 
documented. 
 
5.1.7 
Eastern Cooperative Oncology Group (ECOG) 0-2. 
 
5.1.8 
Adequate organ and bone marrow function as defined by:  
• 
ANC ≥ 1,500/mm3 (1.5 x 109/L); 
• 
Platelets ≥ 100,000/mm3 (100 x 109/L); 
• 
Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥60 ml/min as calculated using 
the method standard for the institution; 
• 
Total serum bilirubin ≤ 1.5 x ULN (<3 ULN if Gilbert’s disease). 
 
5.1.9 
Patient must agree to provide tumour tissue from the most recent pathological tumour specimen. 
Local policy must permit the submission of tissue (blocks or cores). It is the centres responsibility 
to notify CCTG immediately of any changes in local policy that would preclude the submission of 
tissue. Failure to provide tissue blocks or cores will render the patient ineligible. Please refer to 
Section 13.0 for additional information.  
 
5.1.10 Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in 
either English or French. The baseline assessment must be completed within the required timelines, 
prior to registration/randomization. Inability (illiteracy in English or French, loss of sight, or other 
equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. 
However, ability but unwillingness to complete the questionnaires will make the patient ineligible. 
 
5.1.11 Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrolment in the trial to document 
their willingness to participate.  
 
A similar process must be followed for sites outside of Canada as per their respective cooperative 
group’s procedures. 
 
5.1.12 Patients must be accessible for treatment and follow-up. Patients registered on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable geographical 
limits placed on patients being considered for this trial (call the CCTG office (613-533-6430) if 
questions arise regarding the interpretation of this criterion). Investigators must assure themselves 
the patients registered on this trial will be available for complete documentation of the treatment, 
adverse events, response assessments and follow-up. 
 
5.1.13 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization. 


 
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5.1.14 Women of childbearing potential must have agreed to use a highly effective contraceptive method. 
A woman is considered to be of "childbearing potential" if she has had menses at any time in the 
preceding 12 consecutive months. In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or 
with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, 
bilateral tubal ligation, ovarian ablation by radiation therapy or vasectomy/vasectomized partner. 
However, if at any point a previously celibate patient chooses to become heterosexually active 
during the time period for use of contraceptive measures outlined in the protocol, she is responsible 
for beginning contraceptive measures. 
 
Women of childbearing potential receiving combination therapy palbociclib plus tamoxifen or any 
endocrine therapy plus LHRH analogue must use effective contraception as described above. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Appendix I); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
5.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Patients with advanced, symptomatic, visceral spread that are at risk of life threatening 
complication in the short term. 
 
5.2.2 
Patients with symptomatic CNS involvement, meningeal or parenchymal, that is uncontrolled or 
requires steroids.  
 
5.2.3 
Prior treatment with any CDK 4/6 inhibitor. 
 
5.2.4 
Prior treatment with mTOR inhibitors. 
 
5.2.5 
Active second malignancy, regardless of ongoing treatment. 
 
5.2.6 
Any concurrent medical condition that in the opinion of the investigator would interfere with the 
safe administration of the study drug and participation in the study.  
 
5.2.7 
Participation in a prior anti-cancer investigational study within 30 days prior to enrollment. 
 


 
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6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations 
Timing 
History and Physical 
Exam including: 
• History including:  
− 
Diagnosis 
− 
Prior Therapy 
− 
Concurrent Illnesses 
− 
Concomitant Medication 
• Physical Exam including: 
− 
Height and Weight 
− 
Blood Pressure and Pulse 
− 
ECOG Performance Status 
Within 14 days prior to 
randomization 
Hematology 
• CBC 
• Differential 
• Hemoglobin A1c (HBA1c) 
Within 14 days prior to 
randomization 
Biochemistry 
• Serum creatinine  
• Bilirubin (total) 
Within 14 days prior to 
randomization 
Radiology 
• CT/MRI of chest, abdomen and pelvis 
• Bone Scan or PET* 
• Other imagining as necessary to document all 
sites of disease 
Within 28 days prior to 
randomization 
Other Investigations 
• Pregnancy test (if applicable)**  
• ECG 
• Urinalysis 
Within 14 days prior to 
randomization 
Adverse Event 
• Baseline adverse event evaluation (to 
document residual adverse events from 
previous therapy and baseline symptoms) 
Within 14 days prior to 
randomization 
Correlative Studies 
• Submission of representative block or core of 
available tumour tissue from the primary 
breast cancer or metastatic lesion to central 
tumour bank  
On request 
• Whole blood for cfDNA and lymphocyte 
extraction*** 
• Whole blood, serum and plasma for 
banking*** 
Pre Day 1-Cycle 1 dose 
Quality of Life 
• EORTC QLQ-C30 
• Trial Specific Checklist (see Appendix VI) 
Within 14 days prior to 
randomization 
* 
Per Institutional Standard  (mandatory for patients with bone only disease). 
** Pregnancy test (in women of childbearing potential), as part of Pre-Study Evaluation, may include an ultrasound to rule-
out pregnancy. 
*** Mandatory whole blood collection for cell-free DNA and lymphocytes for all patients; Optional whole blood, serum and 
plasma banking for consenting patients. 


 
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ADMIN UPDATE #1: 2017-JUL-05 
7.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All randomizations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
registering/randomizing patients will be provided at the time of study activation and will also be 
included in the “EDC Data Management Guidebook”, posted on the MA.38 trial specific web-site. 
If sites experience difficulties accessing the system and/or randomizing patients please contact the 
help desk (link in EDC) or the MA.38 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. The 
following information will be required: 
• 
trial code (CCTG MA.38) 
• 
investigator CCTG user ID 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
tissue banking consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
• 
stratification factors  
 
7.2 
Stratification 
 
Subjects will be stratified by: 
• 
Centre 
• 
Visceral Metastases: yes versus no 
• 
Duration of exposure to most recent endocrine therapy prior to randomization: ≥ 6 months 
versus < 6 months in the advanced/metastatic setting, or ≥ 24 months versus < 24 months in 
the adjuvant setting 
• 
Planned use of Fulvestrant versus Tamoxifen versus Aromatase Inhibitor 
 
7.3 
Randomization 
 
Randomization will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission cease from the point in time of withdrawal. 
 
 


 
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ADMIN UPDATE #1: 2017-JUL-05 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting randomization. 
 
All randomized patients are to be followed until death or until sites are informed by CCTG that 
further follow-up is no longer required. The follow-up requirements for ineligible patients who 
have received no protocol therapy include submission of the Baseline Report plus a minimal 
follow-up form. Data submission for ineligible participants who have received at least one dose of 
protocol therapy should be followed according to the protocol to allow for treatment and adverse 
event assessment.  


 
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ADMIN UPDATE #1: 2017-JUL-05 
8.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization. 
 
8.1 
Treatment Plan 
 
8.1.1 
Drug Administration 
 
Patients will be randomized to one of the following two arms: 
Arm 
Agent(s) 
Dose 
Route 
Schedule 
Duration 
1 
Palbociclib 
100 mg  
PO 
Daily for 28 day cycle 
Treat until 
progressive 
disease 
Endocrine 
Therapy 
Fulvestrant* 500 mg 
IM 
Days 1 and 15 of cycle 1 and then 
on day 1 of each 28 day cycle 
 
OR 
 
Tamoxifen** 20 mg 
PO 
Daily for 28 day cycle 
 
OR 
 
Aromatase Inhibitor*: 
 
Letrozole 2.5 mg  
Anastrozole 1 mg 
Exemestane 25 mg 
PO  
Daily for 28 day cycle 
2 
Palbociclib 
125 mg  
PO 
Days 1-21 of each 28 day cycle 
Treat until 
progressive 
disease 
Endocrine 
Therapy 
Fulvestrant* 500 mg  
IM 
Days 1 and 15 of cycle 1 and then 
on day 1 of each 28 day cycle 
 
OR 
 
Tamoxifen** 20 mg 
PO 
Daily for 28 day cycle 
 
OR 
 
Aromatase Inhibitor*: 
 
Letrozole 2.5 mg  
Anastrozole 1 mg 
Exemestane 25 mg 
PO 
Daily for 28 day cycle 
* 
In premenopausal women ovarian suppression therapy is required 
** In premenopausal women ovarian suppression therapy is optional 
 
8.2  
Palbociclib 
 
Patients should be instructed to swallow palbociclib capsules whole and not to chew them prior to 
swallowing. No capsule should be ingested if it is broken, cracked, or otherwise not intact. Patients 
should be encouraged to take their dose at approximately the same time each day. 
 
Palbociclib capsules should be taken with food. 
 
Patients experiencing investigational product related toxicity may have their dose modified 
according to Section 8.2.3. 


 
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General rules for palbociclib administration: 
• 
Patients who miss a day’s dose entirely must be instructed NOT to “make it up” the next day. 
• 
Patients who vomit any time after taking a dose must be instructed NOT to “make it up,” and 
to resume treatment the next day as prescribed. 
• 
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the next 
day’s dose.  
 
8.2.1 
Premedication 
 
Premedication is not expected to be required. 
 
8.2.2 
Patient Monitoring  
 
All patients should be closely monitored according to guidelines in Section 9.0 and be advised to 
contact the treating centre in the case of significant toxicities. 
 
8.2.3 
Dose Adjustments  
 
Doses will be reduced for hematologic and other adverse events. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity. Adverse events will be graded 
using the NCI Common Terminology Criteria for Adverse Events Version 4 (CTCAE) (see 
Appendix V). 
 
The major toxic effects of Palbociclib which limit dose are neutropenia, thrombocytopenia, anemia, 
fatigue, constipation, nausea, decreased appetite, vomiting and diarrhea. The guidelines which 
follow outline dose adjustments for several of these toxic effects. If a patient experiences several 
adverse events and there are conflicting recommendations, please use the recommended dose 
adjustment that reduces the dose to the lowest level. 
 
In the event of significant treatment-related toxicity, palbociclib dosing may be interrupted or 
delayed and/or reduced as described below. In the event of multiple toxicities, dose modification 
should be based on the worst toxicity observed. Patients are to be instructed to notify Investigators 
at the first occurrence of any adverse sign or symptom.  
 
Dose modifications may occur in three ways: 
• 
Within a cycle: dosing interruption until adequate recovery followed by dose reduction (if 
required). 
• 
Between cycles: next cycle administration may be delayed due to persisting toxicity when a 
new cycle is due to start. 
• 
At start of the new cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
 
Patients discontinuing palbociclib treatment due to treatment-related toxicity may continue 
endocrine therapy, as per the investigator’s discretion. 


 
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ADMIN UPDATE #1: 2017-JUL-05 
The Palbociclib dose will be decreased according to the schedule displayed in the following table:  
 
 
Starting Dose 
1st Reduction 
2nd Reduction 
3rd Reduction 
Arm 1 
100 mg 
75 mg 
discontinue 
NA 
Arm 2 
125 mg 
100 mg 
75 mg 
discontinue 
 
A dose of 75 mg represents the lowest does that a patient can receive. Dose escalation after a dose 
reduction is not permitted.  
 
8.2.3.1 Palbociclib Dose Management for Hematologic Adverse Events 
 
Applies to Arm 1 (continuous daily dosing) during a cycle. See 8.2.4 for day 1 modifications: 
 
CTCAE Grade 
Palbociclib Dose Management 
Grade 1 
ANC < LLN to 1500/mm3 
Platelets < LLN to 75K/mm3 
• No dose adjustment is required. 
Grade 2 
ANC < 1500 - 1000/mm3 
Platelets < 75K - 50K/mm3 
• No dose adjustment is required. 
Grade 3 
ANC < 1000-500/mm3 
Platelets < 50K - 25K/mm3 
• Reduce by one dose level immediately, and continue treatment.  
• Repeat complete blood count monitoring one week later, continue 
treatment if Grade < 3 for duration of cycle.  
• If grade 3 persists, withhold palbociclib and  initiation of next 
cycle until recovery to Grade ≤ 2.A,B 
• Repeat complete blood count monitoring on day 14 of next cycle. 
• If event recurs next cycle, withhold palbociclib and initiation of 
next cycle until recovery to Grade ≤ 2, and then continue with daily 
dosing schedule of 3 out of 4 weeks. A,B  
Grade 3 neutropenia with  
fever +/- infection  
ANC < 1000 mm3 and  
fever ≥ 38.5º C +/- infection 
• Withhold Palbociclib and initiation of next cycle until recovery to 
Grade ≤ 2 (≥ 1000/mm3).A,B 
• Resume at next lower dose. C 
Grade 4 
ANC < 500/mm3 
Platelets < 25 K 
• Withhold Palbociclib and initiation of next cycle until recovery to 
Grade ≤ 2.A,B 
• Resume at next lower dose. C 
A 
Patients treated on study with fulvestrant may delay initiation of next cycle until Palbociclib is resumed. 
B 
If no recovery within 28 days of dose interruption, discontinue Palbociclib. 
C 
If event recurs at 75 mg daily dose, discontinue Palbociclib. 
 


 
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ADMIN UPDATE #1: 2017-JUL-05 
Applies to daily dosing 3 out of 4 weeks during a cycle. See 8.2.4 for day 1 modifications: 
 
CTCAE Grade 
Palbociclib Dose Management 
Grade 1 
ANC < LLN to 1500/mm3 
Platelets < LLN to 75K/mm3 
• No dose adjustment is required. 
Grade 2 
ANC < 1500 - 1000/mm3 
Platelets < 75K - 50K/mm3 
• No dose adjustment is required. 
Grade 3 
ANC < 1000-500/mm3 
Platelets < 50K - 25K/mm3 
• No dose adjustment is required. 
• Consider repeating complete blood count monitoring one week 
later.  
• Withhold initiation of next cycle until recovery to Grade ≤ 2.A,B 
Grade 3 neutropenia with  
fever +/- infection  
ANC < 1000 mm3 and  
fever ≥ 38.5º C +/- infection 
• Withhold Palbociclib and initiation of next cycle until recovery to 
Grade ≤ 2 (≥ 1000/mm3).A,B 
• Resume at next lower dose. C 
Grade 4 
ANC < 500/mm3 
Platelets < 25 K 
• Withhold Palbociclib and initiation of next cycle until recovery to 
Grade ≤ 2.A,B 
• Resume at next lower dose. C 
A 
Patients treated on study with fulvestrant may delay initiation of next cycle until Palbociclib is resumed. 
B 
If no recovery after 28 days of dose interruption, discontinue Palbociclib.  
C 
If event recurs at 75 mg daily dose, discontinue Palbociclib. 
 
8.2.3.2 Palbociclib Dose Management for Liver and Renal Impairment  
 
Bilirubin Total 
Palbociclib Dose Management 
Grade 1 
(≥ ULN - 1.5 x ULN) 
• No dose adjustment is required 
Grade 2 
(> 1.5 - 3.0 x ULN) 
•  No dose adjustment required (if not considered a safety risk for 
the patient) 
≥ Grade 3 
(> 3.0 X ULN) 
• Hold Palbociclib until recovered to ≤ grade 1 or ≤ grade 2 (if not 
considered a safety risk for the patient).A,B 
• Resume treatment at 1 dose level lower. 
A 
Patients treated on study with fulvestrant may delay initiation of next cycle until Palbociclib is resumed. 
B 
If no recovery within 28 days of dose interruption, discontinue Palbociclib. 
 
Creatinine Clearance 
Palbociclib Dose Management 
Grade 1 
(<LLN - 60 ml/min) 
or 
Grade 2 
(59-30 ml/min) 
• No dose adjustment is required 
≥ Grade 3 (< 30 ml/min) 
• Hold Palbociclib until recovered to ≤ grade 1 or ≤ grade 2 (if not 
considered a safety risk for the patient). A,B 
• Resume treatment at 1 dose level lower  
A 
Patients treated on study with fulvestrant may delay initiation of next cycle until Palbociclib is resumed. 
B 
If no recovery within 28 days of dose interruption, discontinue Palbociclib. 


 
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ADMIN UPDATE #1: 2017-JUL-05 
8.2.3.3 Palbociclib Dose Management for Other Non-hematologic Adverse Events  
 
In case of clinically significant toxicities, please follow the instructions in the table below.  
 
CTCAE Grade 
Palbociclib Dose Management 
Grade 1 or Grade 2 
• No dose adjustment is required.A 
≥ Grade 3  
(if persisting despite medical 
treatment) 
• Hold Palbociclib until recovered to ≤ grade 1 or ≤ grade 2 (if not 
considered a safety risk for the patient).B,C 
• Resume treatment at 1 dose level lower  
A 
In case of a Grade 2 toxicity (excluding alopecia) lasting for ≥ 28 days (both assessed in the presence of 
maximum supportive care as judged by the investigator), dose reduction is recommended for the subsequent 
cycles. 
B 
Patients treated on study with fulvestrant may delay initiation of next cycle until Palbociclib is resumed. 
C 
If no recovery within 28 days of dose interruption, discontinue Palbociclib. 
 
Treatment-related GI tract events have been commonly observed when palbociclib is used as 
monotherapy or in combination with other anticancer therapies. The most frequent treatment-
related events in this system organ class were nausea, diarrhea, and vomiting. Most occurrences 
were mild (Grade 1). Since GI events can contribute to the occurrence of dehydration, decreased 
food intake, weight loss and fatigue, patients should be closely monitored for such events. 
Supportive treatment measures may be initiated as deemed necessary by the treating physician in 
agreement with best local clinical practices. 
 
8.2.4 
Retreatment Criteria (and day 1 of a cycle) 
 
Retreatment with palbociclib following treatment interruption for treatment related toxicity or at 
the start of any new cycle may not occur until all of the following parameters have been met: 
• 
Platelet count ≥ 50,000/mm3. 
• 
ANC ≥ 1000/mm3 and no fever. 
• 
Total Bilirubin ≤ 1.5 x ULN. 
• 
Creatinine Clearance ≥ 30 ml/min. 
• 
Grade ≥ 3 non-hematologic AEs (including nausea, vomiting, diarrhea, and hypertension only 
if persisting despite optimal medical treatment) have recovered to Grade ≤ 1 or ≤ grade 2 (if 
not considered a safety risk for the patient) or baseline. 
 
If a treatment delay results from decline in hematologic parameters, the frequency of blood count 
assessments should be adjusted as clinically indicated. If the retreatment parameters are met within 
28 days of treatment interruption or cycle delay, palbociclib may be resumed. Refer to the Dose 
Adjustment section above for adverse events requiring dose reduction at the time of treatment 
resumption. 
 
If these parameters have not been met after 28 days of dose interruption or cycle delay (including 
the planned 1 week off treatment at the end of the cycle), the patient should permanently 
discontinue palbociclib treatment. Any request for exception to this rule must be discussed with the 
sponsor.  


 
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ADMIN UPDATE #1: 2017-JUL-05 
8.2.5 
Duration of Therapy  
 
Unless unmanageable adverse events occur, treatment with palbociclib will be given until disease 
progression. 
 
8.2.6 
Patient Compliance  
 
Compliance with Palbociclib is very important to the objectives of this study. Study site pharmacy 
staff will make capsule counts at each patient visit during treatment. Patients will be instructed to 
notify study site personnel of missed doses. Dates of missed, held or reduced doses will be recorded 
on the case report form.  
 
8.3 
Endocrine Therapy 
 
Patients will receive either fulvestrant or tamoxifen or aromatase inhibitor hormonal therapy based 
on investigator/patient preference. The selected therapy must be different than the most recent line 
of endocrine therapy. Premenopausal women are required to undergo ovarian suppression therapy 
in addition to fulvestrant or aromatase inhibitor therapy (i.e. surgery, radiation or biochemical 
ablation by LHRH therapy). 
 
Endocrine therapy may be administered as per local policies/procedures. 
 
8.4 
Concomitant Therapy 
 
8.4.1 
Permitted 
 
Patients should receive full supportive care (including bisphosphonates) and palliative care (e.g. 
pain control) as clinically indicated during the trial, including transfusion of blood products, and 
treatment with antibiotics, antiemetics, antidiarrheals and analgesics when appropriate - except for 
those medications identified as “excluded” as listed in Section 8.4.2.  
 
Bisphosphonates for the treatment of osteoporosis or management of existing bone metastases may 
be continued for patients who have been receiving them at a stable dose for at least 2 weeks prior 
to study entry. However, the need to initiate or increase the dose of these therapies during the study 
will be considered as indicative of disease progression leading to the discontinuation of patient 
unless disease progression can be completely ruled out and the exact reason for the use of these 
therapies clearly documented in the patient’s source documentation. 
 
Patients may receive localized radiotherapy on study provided that this therapy is not being given 
because of progression of disease, and provided it is not given to a target lesion. Patients who 
receive radiation therapy to treat a progressing disease lesion, even if the intent is palliative, should 
come off protocol therapy. 
 
8.4.2 
Not Permitted 
 
Concurrent administration with other non-protocol anti-cancer therapy (including hormonal 
therapy), radiation therapy or investigational treatment is not permitted. 
 
 


 
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ADMIN UPDATE #1: 2017-JUL-05 
Cytochrome P450 inhibitors or Inducers: 
Palbociclib is primarily metabolized by liver enzymes, particularly CYP3A4. Co-administration of 
potent inhibitors or inducers of this enzyme can result in significant changes in exposure to 
Palbociclib. For this reason, concomitant administration of agents known to strongly inhibit or 
strongly induce CYP3A4 isoenzymes is not permitted before or during the study. Moderate or weak 
inducers or inhibitors should be used with caution. 
 
A comprehensive list of CYP3A4 inhibitors and inducers is provided in Appendix VIII. The 
Investigator should be alerted if the patient is taking any agent known to affect or with the potential 
to affect selected P450 isoenzymes. If any of the not permitted concomitant medications listed in 
Appendix VIII become necessary for patient management, please contact the CCTG to discuss 
appropriate washout periods and possible drug interactions. 
 
The dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced 
when given concurrently with palbociclib. 
 
Glucocorticosteroids (oral): 
Oral glucocorticosteroid use is not allowed during Palbociclib treatment unless absolutely 
necessary (e.g. for treatment of adverse events) or short-term (up to 2 weeks) because many such 
steroids effectively lower Palbociclib exposure through CYP3A4 interactions. See Appendix VIII 
for a list of prohibited oral glucocorticosteroid medications. 
 
The concomitant use of proton-pump inhibitors (PPI) with palbociclib is allowed. Investigators 
should use caution for patients receiving concurrent treatment with these acid reducing agents, as 
well as H2-receptor antagonists (H2RAs). 
 
CYP2D6 inhibitors: for patients receiving tamoxifen, the concomitant use of CYP2D6 inhibitors 
(including, but not limited to, paroxetine, fluoxetine, sertraline, quinidine) is not recommended. 


 
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9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
9.1 
Evaluation During Protocol Treatment 
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
 History  
 Weight  
 ECOG performance status  
 Blood pressure and pulse 
 Concomitant medications 
 Day 1 of each cycle 
Hematology* 
 CBC 
 Differential 
 Every 2 weeks for the first 2 cycles and 
then on day 1 of each cycle thereafter  
 Hemoglobin A1c (HBA1c)** 
 Day 1 of every 3rd cycle  
(i.e. cycle 3, 6, 9, 12, etc.) 
Biochemistry* 
 Serum creatinine  
 Bilirubin  
 Day 1 of each cycle 
Radiology 
 CT/MRI of chest, abdomen and pelvis 
 Every 12 weeks from randomization (CT 
schedule must be maintained) 
 Bone Scan or PET 
 Every 12 weeks from randomization for 
patients with bone only disease (schedule 
must be maintained) 
 As clinically indicated for all other patients 
 Other imagining as necessary to 
document all sites of disease 
 As clinically indicated 
Other 
Investigations 
 Pregnancy test  
 ECG 
 Urinalysis 
 Ophthalmology exam 
 As clinically indicated 
Adverse Events***  Patients must be evaluated after each cycle for adverse events  
Correlative Studies 
 Whole blood for cfDNA extraction**** 
 Plasma and serum for banking**** 
 Every 12 weeks from randomization and at 
the time of relapse/ progression 
 Tissue biopsy at time of progression 
 At time of progression (if feasible) 
Quality of Life 
 EORTC QLQ-C30 
 Trial Specific Checklists 
 At 4, 8 and 12 weeks and then every 12 
weeks until progressive disease 
* 
Bloodwork Timing: Pre-treatment blood draws may be done the day prior to treatment if necessary, and when treatment 
is to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). In order to ensure 
that nadir counts are not missed, every effort should be made to do interim blood draws within 24 hours of the day 
specified in the protocol. 
** 
If HBA1c results are substantially abnormal, an ophthalmology exam is indicated. 
*** 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
Version 4.0 (CTCAE) (Appendix V). 
**** Mandatory whole blood collection for cell-free DNA for all patients; Optional serum and plasma banking for consenting 
patients. 


 
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9.2 
Evaluation After Protocol Treatment 
 
After discontinuation of study treatment, survival status (including start, stop and type of post study 
anticancer therapies) will be collected at 4 weeks post treatment, then every 3 months (i.e., month 
3, 6, and 9, +/- 14 days) then every 6 months starting at Month 12 (+/- 14 days) from the last dose 
of study treatment.  
 
For patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (i.e. for photographed or palpable lesions) documented disease progression as per 
RECIST definitions will continue to have tumour assessment performed during the follow-up visits 
every 12 weeks (+/-7 days calculated from the date of randomization) until disease progression, 
initiation of new anticancer therapy or discontinuation of patient from overall study participation 
(e.g. death, patient's request, lost to follow-up), whichever occurs first. 
 
For patients who discontinue study treatment due to objective disease progression, telephone 
contact is acceptable (with the exception of the 4 week follow-up visit).  
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
 History  
 at each visit 
 Weight  
 ECOG performance status  
 Blood pressure and pulse 
 at each visit until disease progression 
 Concomitant medications 
 at the 4 week visit only 
Hematology 
 CBC 
 differential 
 Hemoglobin A1c (HBA1c)* 
 at the 4 week visit only 
Biochemistry 
 Serum creatinine  
 Bilirubin  
 at the 4 week visit only 
Radiology 
 CT/MRI of chest, abdomen and pelvis 
 every 12 weeks from randomization 
until disease progression (ct schedule 
must be maintained) then as clinically 
indicated  
 Bone scan or PET 
 every 12 weeks from randomization 
for patients with bone only disease 
(schedule must be maintained) 
 as clinically indicated for all other 
patients 
 Other imagining as necessary to document 
all sites of disease 
 as clinically indicated 
Other Investigations 
 Pregnancy test 
 ECG 
 Urinalysis 
 Ophthalmology exam 
 as clinically indicated 
Adverse Events 
 Adverse events will be recorded and graded 
according to the NCI Common 
Terminology Criteria for Adverse Events 
Version 4.0 (CTCAE) (Appendix V). 
 at each visit** 
continued on next page … 
 
 


 
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Investigations 
Timing 
Correlative Studies 
 Whole blood for cfDNA extraction*** 
 Serum and plasma for banking*** 
 every 12 weeks from randomization 
and at the time of relapse/ progression 
 Tissue biopsy at time of progression 
 at time of progression (if feasible) 
Quality of Life 
 EORTC QLQ-C30 
 Trial Specific Checklists 
 at 4, 8 and 12 weeks and then every 12 
weeks until progressive disease 
* 
If HBA1c results are substantially abnormal, an ophthalmology exam is indicated. 
** 
Only Adverse Events deemed related to protocol therapy (Palbociclib, Fulvestrant or Tamoxifen or AI). 
*** Mandatory whole blood collection for cell-free DNA for all patients; Optional serum and plasma banking for consenting 
patients 


 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions 
 
10.1.1 Evaluable for adverse events. All patients will be evaluable for adverse event evaluation from the 
time of their first treatment. 
 
10.1.2 Evaluable for response. All patients who have received at least one dose of therapy and have their 
disease re-evaluated will be considered evaluable for response (exceptions will be those who 
exhibit objective disease progression prior to the end of cycle 1 who will also be considered 
evaluable). Patients on therapy for at least this period and who meet the other listed criteria will 
have their response classified according to the definitions set out below [Eisenhauer 2009]. 
 
10.1.3 Evaluable for quality of life assessment. All patients who have completed at least one quality of 
life questionnaire are evaluable for quality of life. 
 
10.2 
Response and Evaluation Endpoints 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee. 
 
10.2.1 Measurable Disease. Measurable tumour lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as > 20 mm with chest x-ray 
and as > 10 mm with CT scan or clinical examination. Bone lesions are considered measurable only 
if assessed by CT scan and have an identifiable soft tissue component that meets these requirements 
(soft tissue component > 10 mm by CT scan). Malignant lymph nodes must be ≥ 15mm in the short 
axis to be considered measurable; only the short axis will be measured and followed. All tumour 
measurements must be recorded in millimetres (or decimal fractions of centimetres). Previously 
irradiated lesions are not considered measurable unless progression has been documented in the 
lesion. 
 
10.2.2 Non-measurable Disease. All other lesions (or sites of disease), including small lesions are 
considered non-measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, lymphangitic involvement of lung or skin and abdominal masses 
followed by clinical examination are all non-measurable. Lesions in previously irradiated areas are 
non-measurable, unless progression has been demonstrated. 
 
10.2.3 Target Lesions. When more than one measurable tumour lesion is present at baseline all lesions up 
to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. Note that pathological nodes must meet the criterion of a 
short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be 
considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed (see 10.2.4). At baseline, the sum of the target 
lesions (longest diameter of tumour lesions plus short axis of lymph nodes: overall maximum of 5) 
is to be recorded. 


 
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After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions can not be accurately measured 
but are deemed to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be used. 
 
10.2.4 Non-target Lesions. All non-measurable lesions (or sites of disease) plus any measurable lesions 
over and above those listed as target lesions are considered non-target lesions. Measurements are 
not required but these lesions should be noted at baseline and should be followed as “present” or 
“absent”. 
 
10.2.5 Response. 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
 
Complete Response (CR):  
Disappearance of target and non-target lesions. Pathological lymph nodes must have short axis 
measures < 10mm (Note: continue to record the measurement even if < 10mm and considered CR). 
Residual lesions (other than nodes < 10mm) thought to be non-malignant should be further 
investigated (by cytology specialized imaging or other techniques as appropriate for individual 
cases [ref RECIST 1.1]) before CR can be accepted. Confirmation of response is not required. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of measures (longest diameter for tumour lesions and short axis 
measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non target 
lesions must be non-PD. Confirmation of response is not required. 
 
Stable Disease (SD):  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as 
reference the smallest sum of diameters on study. 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of diameters of measured lesions taking as references the 
smallest sum of diameters recorded on study (including baseline) AND an absolute increase of 
≥ 5mm. Appearance of new lesions will also constitute progressive disease (including lesions in 
previously unassessed areas). In exceptional circumstances, unequivocal progression of non-target 
disease may be accepted as evidence of disease progression, where the overall tumour burden has 
increased sufficiently to merit discontinuation of treatment or where the tumour burden appears to 
have increased by at least 73% in volume. Modest increases in the size of one or more non-target 
lesions are NOT considered unequivocal progression. If the evidence of PD is equivocal (target or 
non-target), treatment may continue until the next assessment, but if confirmed, the earlier date 
must be used. 


 
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Table 1: Integration of Target, non-Target and New Lesions into Response Assessment: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
tumour nodes <10mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least once ≥ 4 wks. 
from baseline 
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
tumour nodes < 10mm 
No Target 
Non-CR/non-PD 
No 
Non-
CR/non-
PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note:  Patients 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”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
10.3 
Response Duration 
 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including baseline). 
 
10.4 
Stable Disease Duration 
 
Stable disease duration will be measured from randomization until the criteria for progression are 
met, taking as reference the smallest sum on study (including baseline). 


 
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10.5 
Methods of Measurement 
 
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. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
10.5.1 Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial and 
≥ 10mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation 
by colour photography including a ruler to estimate the size of the lesion is recommended. If 
feasible, imaging is preferred. 
 
10.5.2 Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 
lesions > 20 mm on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.  
 
10.5.3 CT, MRI. CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). Other specialized imaging or other 
techniques may also be appropriate for individual case [ref RECIST 1.1]. For example, while PET 
scans are not considered adequate to measure lesions, PET-CT scans may be used providing that 
the measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
 
10.5.4 Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
 
10.5.5 Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
 
10.5.6 Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare cases 
if required by protocol (for example, residual lesions in tumour types such as germ cell tumours, 
where known residual benign tumours can remain). When effusions are known to be a potential 
adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumour has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease. 


 
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11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events which are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 11.2 for reporting instructions). These include 
events occurring during the treatment period (until 30 days after last protocol treatment 
administration) and at any time afterwards. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information contained in the investigator brochure. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol agent cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
All deaths, regardless of causality or relation to protocol treatment, must be reported in an expedited 
manner. This includes deaths occurring during the treatment period, and within 30 days after the 
date of the final dose (or at any time if the investigator suspects the death to be treatment related). 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
11.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the MA.38 section of the CCTG website (www.ctg.queensu.ca). 


 
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ADMIN UPDATE #1: 2017-JUL-05 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
MA.38 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the MA.38 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application.  
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting and Exposure Reporting  
 
11.3.1 Pregnancy Prevention 
 
Women of Childbearing Potential (WOCBP) who are enrolled in the trial must have agreed to use 
contraceptive method(s) as described in Eligibility Criterion 5.1.14.  
 
11.3.2 Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants. 
Pregnancies occurring up to 90 days after the completion of study treatment must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form available from the trial webpage. 


 
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ADMIN UPDATE #1: 2017-JUL-05 
Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca).  
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
11.3.3 Exposure Reporting (Non-study Participants) 
 
The investigator is required to report to CCTG any incidence of exposure to study agent(s). 
Exposure is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- study 
participant (an individual who is not otherwise participating in this clinical trial). An example of 
an exposure includes a non-study participant swallowing study medication. The investigator is 
responsible for determining significance, based on the agent to which the individual is exposed.  
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of the 
exposure using the CCTG Exposure Reporting Form available from the trial webpage.  
 
Once informed consent has been obtained, the form should be updated to provide further exposure 
information and to reflect the outcome of the exposure as the information becomes available upon 
appropriate follow-up of the exposed individual. All follow-up reports must be submitted to CCTG 
in a timely manner. A copy of the signed exposure follow-up consent signature page must also be 
submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca).  
 
If the exposure results in death; is life-threatening; requires inpatient hospitalization or prolongation 
of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital 
anomaly/birth defect, then an SAE report must be additionally submitted as described above.  
 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) for 
those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which a causal relationship with protocol treatment cannot be ruled out). 


 
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ADMIN UPDATE #1: 2017-JUL-05 
11.5 
CCTG Reporting Responsibility to Pfizer 
 
Pfizer Inc. will be notified of all protocol reportable serious adverse events (Section 11.1) and 
provided with the corresponding completed CCTG MA.38 CIOMS report within one working day 
(immediately if the event is fatal or life-threatening) of first awareness of the event. Additionally, 
Pfizer Inc. will be notified of all incidences of exposure to Palbociclib during pregnancy or 
lactation.  
 
Pfizer Inc. will also be notified of all deaths on protocol therapy, and within 30 days of the last dose 
of protocol therapy, regardless of causality or relation to protocol treatment within one working 
day of first awareness of the event. 
 
11.6 
Pfizer Reporting Responsibilities 
 
Pfizer will provide CCTG with a copy of the current Investigator’s Brochure and Safety Letters / 
Safety Updates from other studies with Palbociclib reported to regulatory authorities in a timely 
manner. 
 
11.7 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory authorities 
in Canada as reported to the CCTG. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment. The reports will be posted to the CCTG 
trial MA.38 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
MA.38 web based safety monitoring utility and documentation of REB submission must be retained 
in the study binder on site. The REB submission template provided by CCTG can be used to assist 
with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 
 


 
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ADMIN UPDATE #1: 2017-JUL-05 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 8.0. 
• 
Tumour progression as defined in Section 10.0. 
• 
Request by the patient. Efforts should be made to maintain the investigations schedule and 
continue follow-up, even if patients discontinue protocol treatment prematurely and/or no 
longer attend the participating institution. 
 
12.2 
Duration of Protocol Treatment  
 
In the event of progressive disease, patients may continue to receive protocol therapy as long as 
they have not experienced any adverse events requiring permanent discontinuation of study 
medication and are, in the opinion of the investigator, continuing to derive clinical benefit from 
protocol treatment. 
 
Patients will be permitted to remain on protocol therapy beyond formal objective progression until 
the Investigator believes the patient is no longer deriving benefit. Continued use of fulvestrant is 
permitted, but this must be sourced from Canadian commercial supply after progression. 
 
12.3 
Therapy After Protocol Treatment is Stopped 
 
After protocol treatment is stopped, therapy is at the discretion of the investigator. 
 
12.4 
Follow-up Off Protocol Treatment 
 
Refer to Section 9.2 and Appendices I and IV for details of follow up and required investigations. 
 
Annual minimal follow up using the Short Follow-up Report is required for patients who have not 
received any protocol therapy. Ineligible patients who have received at least one dose of protocol 
therapy should be followed as per protocol guidelines outlined in Section 9.  
 


 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
13.2 
Tissue Collection 
 
A detailed Correlative Studies Manual will be provided at centre activation, which will include 
details regarding sample preparation, handling and shipping. 
 
The submission of a representative block of the diagnostic tumour tissue and adjacent normal tissue 
(part of the standard resection), as well as diagnostic tissue submission at the time of progression 
(when feasible), is mandatory for participation on this trial. These should be submitted upon request 
from the Central Tumour Bank.  
 
Where local centre regulations prohibit submission of blocks of tumour tissue, the approval of the 
CCTG must be sought prior to randomization of the first patient to allow cores (two 2 mm cores of 
tumour from the block) to be substituted as an alternative. Failure to submit any tissue samples as 
directed will result in the patient being considered ineligible. Where no previously resected or 
biopsied tumour tissue exists, on the approval of the CCTG, the patient may still be considered 
eligible for the study. 
 
Blocks will be carefully banked as part of the CCTG tissue/tumour bank at Queen’s University in 
Kingston, Ontario. Tumour blocks will be the preferred material to collect, as one of the objectives 
may be to create tissue micro arrays. These will optimize the amount of tissue available to 
investigators and permit the preservation of the tumour block submitted. If, at any time, the 
submitting hospital requires the block to be returned for medical or legal concerns, it will be 
returned by courier on request. 
 
The tissue may be used by researchers now or in the future to better understand the nature of breast 
cancer and how patients respond to treatment. Samples will be used for research purposes only and 
will not be sold. A scientific review process of any proposals to use the tissue will take place and 
any proposals approved will have undergone ethics approval. Patients will not be identified by 
name. The only identification of tissue will be by a patient study number assigned at the time of 
randomization to the trial the surgical/ histology number and/or patient initials. Material issued to 
researchers will be anonymized and only identified by a coded number. 
 
Diagnostic pathology reports are received as part of the supporting documentation required for this 
trial. Receipt of these will initiate a request directly from the Queen’s Department of Pathology to 
pathology departments for a representative tumour block. 
 
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out 
without the expressed consent of the patient.  
 
All patients on whom a diagnostic tumour block is collected will be aware of this retrieval and will 
have given their consent. 
 
Tumour blocks will be requested by the Queen’s Department of Pathology and instructions will be 
included in the request as to where blocks should be sent. The request will be sent to the person 
named in the Correlative Studies Report. Please consult the lab manual for additional information. 
 
 


 
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13.3 
Blood Collection 
 
Whole blood will be collected in Streck tubes and processed for the purpose of cell free DNA 
analysis. This will be collected prior to the start of protocol therapy (pre day 1 – cycle 1) and then 
every 12 weeks after randomization until relapse/progression, and at the time of 
relapse/progression. These samples will also be used for the purposed of lymphocyte extraction 
(baseline sample only). The collection and processing of whole blood for the purposes of collecting 
circulating tumour DNA is a mandatory component of this trial. Failure to submit these samples 
as directed in section 9 of the protocol, and as per the laboratory manual, will result in the patient 
being considered ineligible. Please consult the lab manual for details of specimen collection, 
processing and shipment for this purpose. 
 
Submission of additional whole blood, plasma and serum for the purposes of banking/future 
research is not mandatory for participation in the study, but the participation of all centres is 
strongly encouraged. These samples will be collected at the same time as the cell free DNA 
samples, processed at the sites and will be carefully banked as part of the CCTG tissue/tumour bank 
at Queen’s University in Kingston, Ontario. 
 
At the specified times, participants will provide the following blood specimens: STRECK tubes (whole 
blood in EDTA for cell free DNA extraction), lavender topped tubes (whole blood in EDTA), light 
green topped tubes (containing lithium heparin - for plasma), and red topped tubes (for serum).  
 
Specimens will be processed and stored at participating centers immediately after collection and then 
shipped to a central laboratory, frozen on dry ice, in batches of 10 sets or more (1 set = entire blood 
collection at one patient visit), for subsequent storage and future analysis. Please consult the lab manual 
for specimen collection and shipping details. 
 
Type of Tube 
STRECK Tube  
(1 x 10mL) 
(2.1 teaspoons) 
Lavender Top Tube  
(1 x 6 ml) 
(1.2 teaspoons) 
Light Green Top Tubes 
(2 x 4.5 ml) 
(1.8 teaspoons) 
Red Top Tube 
(2 x 6 ml) 
(2.4 teaspoons) 
To be used for 
Cell free DNA and 
lymphocyte extraction 
(mandatory) 
Whole blood for 
storage for future 
research 
(optional) 
Plasma for storage for 
future research 
(optional) 
Serum for 
storage for 
future research 
(optional) 
 
TOTAL VOLUME DRAWN = 37 ml (7.5 Teaspoons) 


 
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14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
The primary objective of this trial is to estimate the hazard ratio of the progression-free survival for 
two different dose regimens of palbociclib in combination with endocrine therapy (fulvestrant or 
tamoxifen or Aromatase Inhibitor) as second line therapy in women with ER positive, HER2 
negative, advanced/metastatic breast cancer. Second objectives include comparisons of safety and 
tolerability, response rate (in patients with measurable disease), duration of response, clinical 
benefit rate, overall survival between two treatment arms. After stratification by centre, visceral 
metastases (yes versus no), duration of exposure to most recent endocrine therapy prior to 
randomization (≥ 6 months versus < 6 months in the advanced/metastatic setting or ≥ 24 months 
versus < 24 months in the adjuvant setting), and planned use of fulvestrant versus tamoxifen versus 
aromatase inhibitor, patients will be randomized using a minimization method and in a 1:1 ratio to 
two treatment arms: palbociclib 100 mg po daily + fulvestrant or tamoxifen or AI at the standard 
doses/schedules (Arm 1) and palbociclib 125 mg po daily 3 out of 4 weeks + fulvestrant or 
tamoxifen or AI at the standard doses/schedules (Arm 2).  
 
14.2 
Primary Endpoints and Analysis 
 
The primary endpoint is progression free survival (PFS) defined as time from randomization to 
progression or death from any cause. Disease progression will be investigator assessed using the 
RECIST 1.1 criteria [Eisenhauer 2009]. If a patient has not progressed or died at the time of final 
analysis, PFS will be censored on the date of the last disease assessment. All patients randomized 
will be included in the analysis of PFS. The hazard ratio of Arm 1 to Arm 2 and 90% confidence 
interval will be derived from a stratified Cox model adjusting for two stratification factors (visceral 
metastases and duration of exposure to prior endocrine therapy) at randomization. Overall survival, 
defined as time from randomization to the time when death from any cause is documented, will be 
analyzed similarly. 
 
Response and clinical benefit rates are defined respectively as proportion of all randomized patients 
with CR or PR as their best responses or with CR. PR, and SD as their best responses and will be 
compared between two arms using the Cochran-Mantel-Haenszel test adjusting for two 
stratification factors (visceral metastases and duration of exposure to prior endocrine therapy) at 
randomization. For patients with documented CR or PR, duration of response is calculated from 
the time of CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented or death occurs. If a patient has not progressed or died at the 
time of the final analysis, duration of response will be censored on the date of the last disease 
assessment. The difference in duration of response between the two treatment arms will be tested 
using the log-rank test.  
 
All patients who have received at least one dose of study treatment will be included in the safety 
and tolerability analysis. A Fisher’s exact test will be used as needed to compare toxicities between 
the two arms. 
 
14.3 
Sample Size and Duration of Study 
 
Based on the PALOMA 3 study results, a conservative estimated of PFS for the control arm (125 
mg daily, 3/ 4 weeks) is 10 months (Turner 2015).  


 
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The objective of this trial is to estimate the relative efficacy between the two arms. It will not 
include a test of superiority or non-inferiority between the two arms. The sample size is based on 
estimating the hazard ratio (HR) of two arms (experimental vs. control) within a 90% confidence 
interval (CI). For a 1:1 randomization with 1 year accrual and one-year additional follow-up. If we 
observe approximately 58 PFS events in each arm, the upper bound of the 90% CI will be 1.36 
times the estimated HR and the lower bound will be 0.74 times the estimated HR. Assuming a 
median PFS of approximately 10 months for both treatment arms, and duration of accrual and 
follow-up both at 1 year, and a dropout rate of 10%, the study would need to enroll approximately 
90 subjects in each arm.  If the observed hazard ratio is 0.736 or less, then the upper bound of the 
90% confidence interval will be less than 1. 
 
14.4 
Safety Monitoring 
 
Adverse events and their frequencies will be monitored on an ongoing basis by the CCTG Statistics 
and Operations Office personnel and reviewed by the independent Data Safety and Monitoring 
Committee on a 6 monthly basis with more frequent evaluation as required. This data will also be 
presented to the Study Chair, Trial Committee and investigator network at annual investigator 
meetings.  
 
In addition a detailed safety evaluation will be performed after the initial 12 patients on both arms 
are enrolled and followed for 8 weeks to assess safety, tolerability and compliance with therapy, 
including dose reductions and dose discontinuations. Adverse events of importance will include 
grade 3 or 4 neutropenia, febrile neutropenia, infections and death. Accrual will continue during 
this safety assessment.  
 
14.5 
Interim Analysis 
 
There will be no interim analysis for efficacy. 
 
14.6. 
Quality of Life Analyses 
 
The EORTC QLQ-C30 and the Trial Specific Checklist will be mandatory. Scoring of 
questionnaires will be conducted by the central office of CCTG according to the scoring manual of 
the EORTC QLQ-C30. The Trial Specific Checklist items will be scored individually. QOL results 
will be described and exploratory analysis will be conducted to compare the QOL between the 2 
groups. 
 


 
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15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group and Pfizer may be 
credited as authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
• 
In the event of a separate paper dealing with the correlative studies outcomes, the first author 
will generally be the Correlative Sciences Coordinator on the trial committee.  
 
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
“A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions).” 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following study closure the manuscript has 
not been submitted, the central office reserves the right to make other arrangements to ensure timely 
publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
15.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by Pfizer, the 
CCTG Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study 
Chair. Individual participating centres may not present outcome results from their own centres 
separately. Supporting groups and agencies will be acknowledged. 


 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
16.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion.  
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs.  
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately.  
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs.  
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable).  
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation.  


 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in an CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject.  
 
16.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner, exposed individual) should not be collected about or from them unless or until they are a 
willing participant in the research. The rights and protections offered to participants in research 
apply and consent must be obtained prior to collecting any information about or from them. If the 
main consent form adequately addresses the collection of information regarding the outcome of a 
pregnancy of a trial participant, a “Pregnancy Follow-up consent form will not be required by 
CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure Follow-up” can be found 
on the trial webpage. The appropriate consent form must be used to obtain consent from any non-
trial participant (such as the pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 


 
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Obtaining Consent for Research on Children  
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/guardian.  
 
For reporting an exposure, the parent/guardian is required to sign an “Exposure Follow-up” consent 
form (even if they are a participant in the main study) prior to collecting information about the 
child. 
 
16.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why.  
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
16.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP.  
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site.  
 
Essential documents must be retained for 25 years following the completion of the trial at the centre 
(25 years post final analysis, last data collected, or closure notification to REB, whichever is later), 
or until notified by CCTG that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI).  
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 


 
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16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except. 
For details of accessing the EDC system and completing the on-line Case Report Forms please refer 
to the “Registration/Randomization and Data Management Guidebook” posted on the MA.38 area 
of the CCTG web-site (www.ctg.queensu.ca). 
 


 
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17.0 
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McLachlan S, Devins G and Goodwin P. Validation of the European Organization for Research and Treatment 
of Cancer quality of life questionnaire (QLQ-C30) as a measure of psychosocial function in breast cancer 
patients. Eur J Cancer. 34(4):510-7, 1998. 
Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor 
pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 2005; 11 (suppl): 865–
70s. 
Osoba D, Rodrigues G, Myles J, Zee B and Pater J. Interpreting the significance of changes in health-related 
quality-of-life scores. J Clin Oncol16(1):139-44, 1998. 
Paul N, Pater J, Whitehead M and Sadura A. Methods of toxicity data collection: an evaluation of the relative 
effectiveness of the case report flow sheet (fs), the patient symptom diary (sd), and the quality of life 
questionnaire (qlq). Control Clin Trials. 2(5):648, 1991. 
Pfizer Inc. and Affiliates. Investigator’s Brochure, Pembrolizumab (PD-0332991), 2015.  
Tamoxifen Product Label (US FDA). 
Turner N et al. J Clin Oncol 33, 2015 (suppl; abstr LBA502) 
Verma S, Huang Bartlett C, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone 
receptor-positive/HER2-negative advanced metastatic breast cancer : detailed safety analysis from a multicenter, 
randomized, placebo-controlled, phase III study (PALOMA-3). The Oncologist July 2016 : theoncologist.2016-
0097. 


 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Pre-study 
(within 14 days 
prior to 
randomization 
– unless 
otherwise 
specified) 
On 
Treatment 
(Day 1 of 
each cycle) 
On 
Treatment 
(every 12 
weeks) 
End of 
Treatment 
(4 week 
follow-up 
visit) 
Subsequent 
Follow-Up 
Visit (prior 
to Disease 
progression 
At time of 
disease 
progression 
Follow-up 
(following 
disease 
progression) 
Medical History and Physical 
 
 
 
 
 
 
 
History  
X 
X 
 
X 
X 
 
X 
Concurrent Illnesses 
X 
X 
 
X 
 
 
 
Concomitant Medication 
X 
X 
 
X 
 
 
 
Physical exam (height, Weight, 
Blood Pressure, Pulse and ECOG 
Performance Status)  
X 
X 
 
X 
X 
 
 
Hematology5 
 
 
 
 
 
 
 
CBC 
X 
X4 
 
X 
 
 
 
Differential 
X 
X4 
 
X 
 
 
 
HBA1c 
X 
X4 
 
X 
 
 
 
Biochemistry5 
 
 
 
 
 
 
 
Serum Creatinine 
X 
X 
 
X 
 
 
 
Bilirubin (total) 
X 
X 
 
X 
 
 
 
Radiology6 
 
 
 
 
 
 
 
CT/MRI of the chest, abdomen 
and pelvis 
X2 
 
X 
X 
X 
 
 
Bone Scan or PET1 
X2 
As Clinically Indicated 
Other imaging as necessary to 
document all sites of disease 
X2 
As Clinically Indicated 
Other Investigations 
 
 
 
 
 
 
 
Pregnancy Test 
X3 
As Clinically Indicated 
ECG 
X 
As Clinically Indicated 
Urinalysis 
X 
As Clinically Indicated 
Ophthalmology Exam 
As Clinically Indicated 
Adverse Events 
 
 
 
 
 
 
 
Continuously graded and recorded 
according to CTCAE v4.0  
X 
X 
 
X11 
X11 
 
X11 
Correlative Studies 
 
 
 
 
 
 
 
Archival tissue blocks 
X 
 
 
 
 
X10 
 
Whole blood for cell-free DNA  
X7 
 
X7 
 
X7 
X 
 
Whole blood for lymphocytes 
X 
 
 
 
 
 
 
Whole blood for banking 
X8 
 
 
 
 
 
 
Serum and plasma for banking 
X7 
 
X7 
 
X7 
X 
 
Quality of Life 
 
 
 
 
 
 
 
EORTC QLQ-C30 
X 
X9 
X9 
X9 
X9 
 
 
Trial Specific Checklist 
X 
X9 
X9 
X9 
X9 
 
 
footnotes on next page … 
 
 


 
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1 
Per Institutional Standard (mandatory for patients with bone only disease at baseline and every 12 weeks from 
randomization – schedule must be maintained). 
2 
Within 28 days prior to randomization. 
3 
Pregnancy test (in women of childbearing potential), as part of Pre-Study Evaluation, may include an ultrasound to rule-out 
pregnancy. 
4 
CBC and differential required every 2 weeks for the first two cycles, and then on day 1 of each cycle thereafter. HBA1c is 
required day 1 every 3rd cycle (i.e. cycle 3, 6, 9, 12, etc.). 
5 
Bloodwork Timing: Pre-treatment blood draws may be done the day prior to treatment if necessary, and when treatment is 
to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment). In order to ensure that 
nadir counts are not missed, every effort should be made to do interim blood draws within 24 hours of the day specified in 
the protocol. 
6 
Every 12 weeks from randomization until progression (CT schedule must be maintained). 
7 
Mandatory whole blood samples for cell free DNA and optional serum and plasma banking for consenting patients are 
required to be obtained at the following time points; Baseline and then every 12 weeks from randomization.  
8 
Optional whole blood banking for consenting patients only. Only required to be obtained at baseline. 
9 
Required At 4, 8 and 12 weeks and then every 12 weeks until progressive disease. 
10 If feasible. 
11 Only Adverse Events deemed related to protocol therapy (Palbociclib, Fulvestrant or Tamoxifen or AI). 


 
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
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. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 


 
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ADMIN UPDATE #1: 2017-JUL-05 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Distribution 
Palbociclib will be supplied by Pfizer Inc. and distributed by Bay Area Research Logistics (BARL) to 
participating centres.  
 
Fulvestrant will be supplied for this study, and distributed by Bay Area Logistics (BARL) to participating 
centres.  
 
All other drugs for this protocol are commercially available and sourced from the Canadian market. 
 
Drug Labelling  
Drug supplies for this study will be labelled in accordance with Health Canada regulations.  
 
Initial Drug Supply: 
Once a centre is locally activated (following receipt and review of all required documentation), the CCTG 
will authorize a start-up supply of Palbociclib to be shipped directly to the centre. The drug will be shipped 
to the centre within 5 working days of local activation. Drug accountability and drug re-order forms will be 
included with the drug shipment and are also available on the trial website.  
 
Please note that sites must request their initial supply of palbociclib (and fulvestrant) from BARL directly. 
 
Drug Ordering (Re-Supply)  
Fax a copy of the re-order form (available on the trial website) to the distributor. 
 
Drug Accountability 
The investigational products are to be prescribed only by the investigator and co-investigators on the 
participants list. Under no circumstances will the investigator allow the drug to be used other than as 
directed by the protocol. Accurate records must be maintained accounting for the receipt of the 
investigational product and for the disposition of the product (Drug Accountability Log). 
 
Drug Destruction  
Expired/used study drug may be destroyed as per local standard operating procedures. Destruction of 
expired/used drug must be documented on the Drug Accountability Log and a copy of the destruction 
certificate kept on file in the pharmacy. Instructions for return or destruction of unused drug will be supplied 
at the time of expiry and at trial closure. 
 
** PLEASE NOTE ** 
DRUG FROM THIS SUPPLY IS TO BE USED ONLY 
FOR PATIENTS REGISTERED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a satellite 
pharmacy, provided separate drug accountability records are maintained in each pharmacy. However, study 
drug may NOT be transferred to pharmacies or physicians outside the participating centre. 


 
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ADMIN UPDATE #1: 2017-JUL-05 
APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization and will apply to all eligible patients.  
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For details of 
accessing the EDC system and completing the on-line Case Report Forms please refer to the “CCTG EDC 
Generic Data Management Guidebook” posted on the MA.38 area of the CCTG web-site 
(www.ctg.queensu.ca). 
 
The electronic CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Required at 
To be completed electronically 
Supporting Documentation 
Required* 
Eligibility Checklist 
 
Within 2 weeks of randomization 
Consent form**, relevant 
pathology report(s), 
relevant radiology 
report(s) 
Baseline Report 
 
Within 2 weeks of randomization 
Correlative Studies 
Report 
(Tumour and Blood) 
Continuous 
running-log folder  
See sections 6.0 and 
9.0  
Information pertaining to 
baseline/pretreatment (i.e. tumour 
specimen information and blood collection 
for correlative studies) must be completed 
within 2 weeks of randomization.  
Tissue to be submitted immediately upon 
request.  
Consent form** 
 
Diagnostic pathology 
report  
(for tumour tissue only)  
Information pertaining to post 
randomization tissue and blood collection 
samples for correlative studies and 
banking should be completed within 2 
weeks after collection of final blood 
specimen.  
Information pertaining to skin/blood 
collection for Pharmacokinetics/ 
Pharmacodynamics must be completed in 
EDC in real-time, as soon as the sample is 
collected.  
Treatment Report 
Every 28 days 
Within 2 weeks of the end of the cycle 
Relevant radiology reports  
End of Treatment 
Report 
End of treatment 
Within 2 weeks of the end of treatment 
None 
Relapse/Progression 
Report 
Upon disease 
relapse/progression 
Within 4 weeks of progression 
Relevant radiology and 
pathology reports  
4 Week Follow-up 
Report 
4 weeks from the 
end of the last cycle 
Within 2 weeks of the follow-up visit 
Relevant radiology reports  
Follow-up Report 
Every 12 weeks 
Within 4 weeks of the follow-up visit 
Relevant radiology reports  
Short Follow-up 
Report 
Every 12 weeks 
Within 4 weeks of the follow-up visit 
None 
Death Report 
When patient 
dies**** 
Within 4 weeks of the patient’s death 
Copy of post-mortem 
report if performed 
SAE Report*** 
At time of event 
Within 1 working day 
None 
* 
Scan and upload into the EDC Supporting Document Upload Tool 
** 
For Canadian centres, it is acceptable to submit only the signature page(s) of the main consent and only the check box page(s)/signature 
page(s) of the optional consent provided that the version date of the consent form is indicated.  
*** See section 11.0 Serious Adverse Event Reporting for details. 
****  It is the investigator’s responsibility to investigate and report the date and cause of death of any patient entered into this trial.  


 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (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 website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


 
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APPENDIX VI - QUALITY OF LIFE ASSESSMENT 
 
Introduction 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as 
a guide for the administration of the Quality of Life questionnaire. 
 
1. Preamble 
 
Quality of life data are collected for research purposes, and will usually not be used for the patient’s 
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must 
be completed by the patient only, without translation, coaching or suggestions as to the "correct" answer 
by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or pre-registration (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 


 
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If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the reason(s) 
on the appropriate case report forms. 
 
2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire as soon as it has been completed, check to see that each 
question has been answered and gently remind the patient to answer any inadvertently omitted 
questions. If a patient states that s/he prefers not to answer some questions and gives a reason(s), the 
reason(s) should be noted on the questionnaire. If a specific reason is not given, this also should be 
noted on the questionnaire. 
 
3. Assessments During Treatment 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, and 
prior to treatment on the day of treatment, as required by the schedule in the protocol. If the patient 
does not have a doctor visit scheduled, or if it was not possible for the patient to complete the 
questionnaire before being seen by the doctor, s/he should still complete the questionnaire prior to 
treatment. 
 
4. Assessments During Follow-up 
 
The quality of life questionnaire should be given to the patient before being seen by the doctor, on 
follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel 
unwell. In that case, you may express sympathy that things are below par, but state that this 
is exactly the information we require if we are to understand more about how quality of 
life is affected. You may also remind them that it takes only a few minutes to complete. 
 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!  
 
5. What If . . .  
 
The patient should complete the questionnaires at the clinic. The exception is that the design of some 
trials may require the patient to take the questionnaire home with them after leaving the clinic, and 
complete it on the specific day, because a return visit to the clinic is not scheduled. 
 
There may be circumstances when the patient does not complete the questionnaire as required in the 
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can still 
be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient.  


 
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Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one: 
 
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the 
questionnaire in a timely fashion. Record the date it was mailed and the date received on the 
questionnaire. 
 
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over 
the phone. If the patient agrees, read out the questions and range of possibilities, and record the 
answers. Make a note on the questionnaire that the questionnaire was completed over the phone. 
 
If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular 
visit(s). 
 
Ensure that the patient has a supply of questionnaires, with instructions about when to complete 
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at 
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires 
to the patient. Written instructions may help ensure that the patient stays on schedule as much as 
possible.  
 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and 
failing to comply with the patient's wishes is likely to result in the questionnaire not being completed 
at all, then the patient may take the questionnaire home with instructions that it is to be completed the 
same day. When the questionnaire is returned, the date on which the questionnaire was completed 
should be noted and a comment made on the questionnaire as to why the patient took it away from the 
clinic before completion.  
 
6. Waiving the Quality of Life Component 
 
The only time that we will not require a patient to complete the quality of life questionnaires is if s/he 
is not literate in either English or French (or other languages that the questionnaire may be available 
in). In other words, if the assistance of a translator is required to comprehend the questions and reply, 
the questionnaires should not be completed. Translation of the questions is not acceptable. Please 
indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 


 
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8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or 
French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire 
should be read to them and the answers recorded by a health care professional (e.g. preferably the 
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who 
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient 
is completing the questionnaire at home, and a telephone interview by the clinical research associate is 
not possible, then a spouse or friend may read the questions to the patient and record the answers. 
However, this method should be a last resort, and the spouse or friend should be instructed to not coach 
or suggest answers to the patient. Whichever method is used, it should be recorded on the questionnaire. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 
 


 
 
Quality of Life Questionnaire – ENGLISH  
 
CCTG Trial: MA.38 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization 
During chemotherapy:  
 Week 4      Week 8      Week 12      Week 24       Week 36      Week48      Week 60 
 
 Week _____  
Off Treatment: 
 Week 4      Week 8      Week 12      Week 24      Week 36      Week48      Week 60 
 
 Week  ______ 
* Note: Questionnaire is not required to be completed at time of relapse/new primary malignancy or afterwards. 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
 
      yyyy          mmm        dd 
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 
 
CCTG use only 
Logged: _______ 
______ - ____ - ____ 
Study Coord: _______ 
______ - ____ - ____ 
Res Assoc: _______ 
______ - ____ - ____ 
Data Ent’d: 
_________ 
Verif: 
_________ 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.38 
Page 1 of 4 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (MA.38) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.38. EORTC QLQ-C30 
Page 2 of 4 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.38. EORTC QLQ-C30 
Page 3 of 4 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
 
 
 


This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial MA.38 Trial-Specific Checklist 
Page 4 of 4 
 
Patients sometimes report that they have the following symptoms. Please indicate the extent to which 
you have experienced these symptoms during the past week. 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. Did you have a sore mouth? 
1 
2 
3 
4 
 
 
 
 
 
32. Have you had tingling hands or feet? 
1 
2 
3 
4 
 
 
 
 
 
33. Were your fingers or toes numb (loss of feeling)? 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
Please check to make sure you have answered all the questions. 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 
 
 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
68 
CONFIDENTIAL 
APPENDIX VII - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS 
 
The 7th Edition of the TNM Classification of Malignant Tumours has recently been released. To facilitate 
this process, educational resources have been made available to promote the use of staging (visit 
http://www.cancerstaging.org). These staging criteria should be used for new trials. 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
69 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
APPENDIX VIII - PROHIBITED MEDICATIONS 
 
Drug class 
Agent 
Wash-out 
(period of time that the medication 
should be discontinued prior to 
administration of the first dose of 
protocol treatment)* 
Inducers of CYP3A4 
 
 
Antibiotics  
All rifamycin class agents (rifampicin, rifabutin, 
rifapentine)  
7 days  
Anticonvulsants  
Phenytoin, carbamazepine, barbiturates 
(phenobarbital)  
7 days  
Antiretrovirals  
Efavirenz, nevirapine, tipranivir, etravirine  
7 days  
Glucocorticoids (oral)  
Chronic use of cortisone (> 50mg), 
hydrocortisone (> 40 mg), prednisone or 
prednisolone (> 10 mg), methylprednisolone or 
triamcinolone (> 8 mg), betamethasone or 
dexamethasone (> 1.5 mg). Glucocorticoid daily 
doses (oral) ≤ 1.5 mg dexamethasone (or 
equivalent) are allowed. Short term steroid use 
(up to 2 weeks) is allowed.  
7 days  
Other  
St. John’s Wort, modafinil  
7 days  
Inhibitors of CYP3A4 
 
 
Antibiotic 
clarithromycin, erythromycin, troleandomycin, 
flucloxacillin  
7 days  
Antifungals  
itraconazole, ketoconazole, fluconazole (> 150 
mg daily), voriconazole  
7 days  
Antiretrovirals, Protease 
Inhibitors  
delaviridine, nelfinavir, amprenavir, ritonavir, 
indinavir, saquinavir, lopinivir, atazanavir  
7 days  
Calcium channel blockers  
verapamil, diltiazem  
7 days  
Antidepressants  
nefazodone, fluvoxamine  
7 days  
GI Agents  
Cimetidine, aprepitant  
7 days  
Other 
grapefruit, grapefruit juice, seville oranges, star 
fruit, papaw, amiodarone 
7 days 
 
Miscellaneous 
 
 
Herbal or dietary 
supplements and traditional 
Chinese medicines 
Ginkgo biloba, kava, grape seed, valerian, 
ginseng, Echinacea, evening primrose oil.  
14 days  
* 
All patients must have observed the specified washout period for all prohibited drugs prior to randomization.. 
 
 


 
PROTOCOL DATE: 2015-NOV-09 
 
CCTG TRIAL: MA.38 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
ADMIN UPDATE #1: 2017-JUL-05 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
ELIGIBILITY CHECKLIST 
Must be completed prior to 
allocation. 
Sue Steacy 
Clinical Trials Assistant, CCTG 
Email: ssteacy@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Chad Winch 
Study Coordinator, CCTG 
Email: cwinch@ctg.queensu.ca 
or: 
Dr. Wendy Parulekar 
Senior Investigator, CCTG 
Email: wparulekar@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Anil Abraham Joy 
Email: anil.joy@ahs.ca 
780-432-8762 
780-432-8888 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for 
details of reportable events. 
Chad Winch 
Study Coordinator, CCTG 
Email: cwinch@ctg.queensu.ca 
613-533-6430 
613-533-2941 
DRUG ORDERING 
See Appendix III for full details. 
See Appendix III and trial website: www.ctg.queensu.ca 
 

SAP_000.pdf: 
Final Statistical Analysis Plan for BL12 
 
A MULTICENTRE RANDOMIZED PHASE II TRIAL COMPARING NAB-PACLITAXEL  
TO PACLITAXEL IN PATIENTS WITH ADVANCED UROTHELIAL CANCER  
PROGRESSING ON OR AFTER A PLATINUM CONTAINING REGIMEN 
CCTG TRIAL BL12 
 
 
 
SUPPORTED BY: Celgene 
 
 
 
 
 
Prepared by: 
 
Trial Statistician: Keyue Ding, Ph. D 
 
August 18, 2017 
 


 
1. Introduction and background 
5 
1.1 Study plan and its amendment, and interim analyses during the Conduction 
5 
2. Methods and Analyses 
5 
2.0 Dataset 
5 
2.1 
Analyses populations 
5 
2.2 
Conventions for Calculating Key Data 
5 
2.3 
Analysis Conventions 
6 
2.4. 
Randomization and Pre-treatment Characteristics 
6 
2.4.1 
Definitions and Variables 
6 
2.4.1.1 
Accrual 
6 
2.4.1.2   Randomization/Stratification 
6 
2.4.1.3 
Ineligibility and Significant Protocol Deviations (Table 5) 
6 
2.4.1.4 
 Summary of Follow-up 
6 
2.4.1.5 
           Patient Characteristics 
6 
2.4.1.6            Baseline symptoms (Table 8) 
7 
2.4.1.8 
               Baseline Hematology/Biochemistry (Table 9) 
7 
2.4.2     
Analysis of pre-treatment characteristics 
7 
2.5 
    Efficacy 
7 
2.5.1 
    Definitions and Variables 
7 
2.5.1.1 
 Progression free survival 
7 
2.5.1.2 Overall survival 
7 
2.5.1.3 Clinical benefit response rate 
7 
2.5.1.4 Objective response rates (complete or partial response (ORR)) 
8 
2.5.1.5 Time to response 
8 
2.5.1.6 The duration of response 
8 
2.5.2          
Analysis of Key Parameters 
8 
2.5.2.1 Progression Free Survival 
8 
2.5.2.2 Overall survival 
9 
All analysis for PFS will be performed for OS. And a table summarizes the death causes by arm. 
9 
(Table 14-16). 
9 
2.5.2.3 Clinical benefit response rate 
9 
2.5.2.4 Objective response rates 
9 
2.5.2.5 Time to response 
9 
2.5.2.6 The duration of response 
9 
2.6    Drug Exposure 
9 
2.6.1 
Definitions and Variables 
9 
2.6.1.1 
Duration of Study Therapy in months, cumulative dose 
9 
2.6.1.2   Cumulative dose, dose intensity and relative dose intensity of Nab-Paclitaxel / Paclitaxel 
9 
2.6.1.3 
    Dose reduction, interruption or discontinuation 
10 
2.6.2            Analysis 
10 
2.7  Safety 
10 
2.7.1     
Definitions and variables 
10 
2.7.1.1 
            Laboratory tests 
10 
2.7.1.2 
Toxicity/adverse event/intercurrent illness 
11 
2.7.2           Analysis 
11 
2.8     Concomitant medications, transfusion and hospitalization 
11 
2.8.1           Definition and Variables 
11 
2.8.2          
Analysis 
11 
2.9 
Off- protocol therapies 
11 
2.9.1    
Definitions and Variables 
11 
2.9.2      
Analysis 
12 


2.10 Quality of life 
12 
2.10.1 Definitions and Variables 
12 
2.10.1.1 
EORTC QLQ- C15-PAL 
12 
2.10.1.2 
The FACT-Taxane questionnaire 
13 
2.10.2 Analysis 
13 
2.10.2.1 
Determination of Assessment Times 
13 
2.10.2.2 
Calculation of Compliance Rates 
13 
2.10.2.3 
Cross-sectional analysis 
14 
2.10.2.4 
 QOL response analysis 
14 
3. Tables 
15 
Table 1:  Accrual by Center 
15 
Table 2:  Accrual by Stratification Factor at Randomization 
16 
Table 3:  Treatment as Randomized Versus as Treated at Cycle 1 
17 
Table 4:  Discrepancies between Stratification Level as Randomized and at Baseline 
17 
Table 5:  Eligibility, Reasons for Ineligibility and Major Protocol Violations 
18 
Table 6:  Month of Last Follow-up for all Patients and min and max FU for alive patients 
18 
Table 7:  Pretreatment Characteristics at Baseline 
19 
Table 8:  Baseline Signs and Symptoms 
20 
Table 8:  Baseline Hematology/Biochemistry 
21 
Table 10:  Log rank and Cox Regression Model for Progression Free Survival 
22 
Figure 1: K-M curves of PFS by treatment arm 
23 
Table 11 Progression Summary 
23 
Table 12:  Progression free Survival by Subsets 
24 
Table 13:  Anti-Cancer Therapy Received After Progression 
25 
Figure 2: K-M curves of OS by treatment arm 
25 
Table 14:  Log rank and Cox Regression Model for Overall Survival 
26 
Table 15 Death Summary 
27 
Table 16:  Overall Survival by Subsets 
27 
Table 17:  Clinical benefit response rate 
28 
Table 18:  Cochran Mantel Haenszel and Logistic Regression Model for Clinical benefit response rate 
29 
Table 19:  Clinical benefit response rate According to Baseline Stratification Factors 
30 
Table 20:  Cochran Mantel Haenszel and Logistic Regression Model for best response rate 
31 
Table 21:  Response rate According to Baseline Stratification Factors 
32 
Table 21: Time to response 
32 
Table 22:  Duration of Response 
33 
Table 23: Total treatment Duration and dose of  Nab-Paclitaxel /Paclitaxel 
33 
Table 24 : Dose Reduction, Interruption or Discontinuation 
34 
Table 25:  Hematology: Worst Ever Grade per Patient on Study 
35 
Table 26:  Biochemistry:  Worst Grade per Patient over Study 
36 
Table 27:  Toxicity/Adverse Events/Intercurrent Illness (worst ever over the study) 
37 
Table 28:  Worst Ever Toxicities/Adverse Event/Intercurrent Illness which are Serious, Fatal Only, Leading 
to Hospitalization 
38 
Table 29:  Worst Ever Toxicity/Adverse Event/Intercurrent Illness Led to Dose Discontinuation 
39 
Table 30:  Worst Ever Toxicity/Adverse Event/Intercurrent Illness Led to Dose Interruption 
40 
Table 31:  Worst Ever Toxicity/Adverse Event/Intercurrent Illness Led to Dose Reduction 
41 
Table 32:  Deaths on Study within 30 Days 
41 
Table 33:  Summary of Supportive and Concomitant Medications and Therapy, Transfusion and 
hospitalization 
42 
Table 34:  Reason Off-protocol Therapy 
43 
Table 35:  Compliance (Received/Expected) with QOL Assessment by Treatment Arm 
43 
Table 36:  Baseline Score for Each Domain/item 
44 
Table 37:  Mean QOL Change Scores from Baseline for each Domain/item at Each Assessment Time 
44 


Table 38:  Results for QOL Response Analyses 
45 
 
 


1. Introduction and background  
BL12 is a randomized, open-labelled, multicentre trial for patients with advanced urothelial cancer failing one line of 
platinum based therapy were randomized to either nab-paclitaxel or paclitaxel with a 1:1 ratio. The primary objective 
is to compare progression free survival (PFS) between treatment arms among all randomized patients. Patients were 
randomized stratified by study center, performance status (0,1 vs. 2), liver metastases (yes vs. no), lymph node 
metastases only (yes vs. no), hemoglobin (< 100 g/L vs. ≥ 100 g/L) and interval from last platinum based 
chemotherapy (≤ 6 months vs. > 6 months). Secondary objectives include comparing overall survival (OS), objective 
response rate (ORR), clinical benefit rate (ORR+SD ≥ 12 weeks), time to response and response duration, safety and 
tolerability, QoL outcomes, and an economic analysis. Exploratory objectives include correlative biology (biological 
specimens and questionnaire) studies. 
 
1.1 Study plan and its amendment, and interim analyses during the Conduction 
 
Assuming a median progression free survival of 4 months with paclitaxel, the study was designed to detect a 
one third reduction in the hazard of disease progression with nab-paclitaxel (PFS HR=0.67) which translates 
into a 50% median PFS improvement of 2 months (i.e. from 4 to 6 months). Using a 1- sided 5% significance 
test with 80% power, 155 events are required. This would be achieved with an accrual rate of 5.5 patients/ 
month for 36 months with a follow-up period of 4 months. The estimated sample size is approximately 199 
patients which would allow for a 5% lost to follow-up or withdrawal of consent. 
 
The trial was activated on Jan. 27 of 2014, and the patient’s accrual is still ongoing with 174 already been 
accrued to trial by Nov. of 2016.  There is no interim analysis for this trial. This document is to describe the 
statistical analysis plan for the final analysis of the study. The analysis will include the primary and secondary 
efficacy endpoints, safety and QoL analysis, while the economic analysis and correlative study will be analyzed 
separately.  
 
2. Methods and Analyses 
 2.0 Dataset 
Clinical data cutoff date for patients included in this analysis, and date of freezing dataset will be given. 
2.1 
Analyses populations 
 
Analysis populations for this analysis will be included both the intention to treat (ITT) population (i.e. all as 
randomized patients) and as treated population with data included as specified by the data cutoff point for this 
analysis. 
 
Analysis of pretreatment characteristics and all other efficacy analysis such as PFS, OS, ORR, and other 
efficacy outcomes will be based on ITT population. While for safety analyses, it will be based on patients who 
have received at least one dose of study medication, i.e., as treated population. 
2.2 
Conventions for Calculating Key Data  
Baseline evaluations are those collected closest, but prior to or on the day of randomization. 
 
When either day or month of a date is missing, the missing day and/or month will be imputed by the midpoints 
within the smallest known interval.  For example, if the day of the month is missing for any date used in a 
calculation, the 15th of the month will be used to replace the missing day.  If the month and day of the year are 
missing for any date used in a calculation, the first of July of the year will be used to replace the missing day. 


2.3 
Analysis Conventions  
All comparisons between treatment arms will be carried out using a two-sided test at an alpha level of 5% 
unless otherwise specified.  There are no formal adjustments will be made for the multiplicity of inferences for 
other multiple clinical endpoints. Thus, if the primary endpoint is not significant at the 5% 1-sided test, the rest 
of the analyses are purely exploratory in nature.  
 
The following baseline factors that will be used to adjust the analyses where appropriate are listed as follows: 
ECOG performance status (0,1 vs. 2), liver metastases (yes vs. no), lymph node metastases only (yes vs. no), 
hemoglobin (< 100 g/L vs. ≥ 100 g/L) and interval from last platinum based chemotherapy (≤ 6 months vs. > 6 
months) (*Add missing/unknown category whenever appropriate). 
2.4. 
Randomization and Pre-treatment Characteristics 
2.4.1 Definitions and Variables  
2.4.1.1 Accrual 
Χ 
 Number (%) of randomized patients per study center. (Table 1) 
2.4.1.2   Randomization/Stratification  
Χ 
ECOG performance status (0,1 vs. 2), 
Χ 
liver metastases (yes vs. no),  
Χ 
lymph node metastases only (yes vs. no),  
Χ 
hemoglobin (< 100 g/L vs. ≥ 100 g/L) and  
Χ 
interval from last platinum based chemotherapy (≤ 6 months vs. > 6 months). (Table 2) 
(Note: An unknown/missing category will be added to each factor whenever is necessary.) 
 
Χ 
Treatment assigned at randomization will be compared with the actual treatment received 
during the first cycle to identify any discrepancies (Table 3) 
Χ 
       Baseline patient characteristics will be compared with the patient’s corresponding 
stratification assignment to identify any discrepancies (Table 4) 
 
2.4.1.3 Ineligibility and Significant Protocol Deviations (Table 5) 
Χ 
 Eligible patients: % yes, no  
Χ 
Reasons for ineligibility: % for each reason and combination of reasons of ineligibility. The 
process for verifying eligibility criteria is detailed in the data management plan for this study.  In 
the final report, a distinction between minor deviation and truly ineligible will be made.  Only 
those categories with truly ineligible patients will be included in the table. 
2.4.1.4  
Summary of Follow-up 
A table showing the median, min and max follow-up will be presented by treatment group and for all patients 
included in analysis. (table 6) 
 
2.4.1.5            Patient Characteristics  
 Χ 
Race: % Caucasian, African American, Asian, Hispanic or Latino, others, unknown (or refusal)  
Χ 
  Age: < 40 vs 40 to <50 vs. 50 to < 60 vs 60 to < 70 vs. 70+.  
               < 65 vs. ≥ 65, median, min and max;   
Χ 
Gender: # (%), Male vs. Female;  
Χ 
Prior Immunotherapy (No vs. Yes) (Table 7). 
        *Add missing or unknown as a category where it is appropriate.  


 
2.4.1.6            Baseline symptoms (Table 8) 
The CTC version 4.0 will be used for the categorization of all baseline symptoms.  
Χ 
  Any event per patient: % yes, no 
Χ  
Type of event by grade (1, 2, 3, 4, unknown) 
 
2.4.1.8                Baseline Hematology/Biochemistry (Table 9) 
CTC grades will be used to summarize the baseline hematology/biochemistry data.  
 
 
% by CTC grades 
Χ 
WBC 
Χ 
Anemia 
Χ 
platelets 
Χ 
Neutrophils 
Χ 
Serum creatinine 
 
Χ 
bilirubin 
Χ 
ALT (SGPT) 
 
2.4.2     
Analysis of pre-treatment characteristics 
No formal statistical tests will be performed to assess homogeneity of baseline characteristics between the arms.  
Categorical variables will be tabulated by treatment arm and for all patients.  Continuous variables (e.g., age) 
will be presented using summary statistics (n, median, min and max) or specified cutoff categories by treatment 
arm and for all patients. Analyses will be based on all randomized patients by arm based on the ITT population. 
 
2.5 
    Efficacy 
2.5.1     Definitions and Variables 
2.5.1.1  Progression free survival  
Progression free survival is defined as the time from randomization to the date of the first documented disease 
progression or death due to any cause. A patient who stops treatment with study drug and goes on to receive 
alternative therapy for UC, prior to documentation of disease progression or death, will be censored on the last 
date of assessment prior to receive alternative therapy when there was no documented disease progression. If a 
patient has not progressed, died, or received alternative therapy for UC, PFS will be censored on the date of the 
last disease assessment. 
2.5.1.2 Overall survival   
Overall survival is defined as the time interval between the date of randomization and the date of death from 
any cause. Patients who are still alive at the time of the final analysis or who have become lost to follow-up will 
be censored at their last date known to be alive. 
2.5.1.3 Clinical benefit response rate 
The clinical benefit response rate will be calculated for all patients. It is defined as the ratio of the total number 
of patients who achieve a complete or partial response (patients with at least one measurable lesion at baseline) 
plus those patients who have stable disease for at least 12 weeks (all patients - with or without measurable 
disease at baseline) based on the Response Evaluation Criteria in Solid Tumours – RECIST criteria to all 
randomized patients by treatment arm.  


2.5.1.4 Objective response rates (complete or partial response (ORR)) 
 
Objective response rates (complete or partial response (ORR)) will be calculated for all patients. It is defined as 
the ratio of total number of patients who achieve a complete or partial response (patients with at least one 
measurable lesion at baseline) based on the Response Evaluation Criteria in Solid Tumours – RECIST criteria 
to all randomized patients by treatment arm.  
 
2.5.1.5 Time to response 
Time to response is defined as the time from the date of the first dose of study drug until the first objective 
status assessment of CR/PR among those who achieved a CR or PR. For the rest of patients, it will be censored 
at last disease assessment date.  
 
2.5.1.6 The duration of response 
The duration of response is defined as the time from the date of the first documentation of CR or PR to the time 
disease progression or death is documented (whichever comes first). A patient who stops treatment with study 
drug and goes on to receive alternative therapy for UC, prior to documentation of disease progression or death, 
will be censored on the date alternative therapy began. If a patient has not progressed or died or received 
alternative therapy, the duration of response will be censored on the date of last known disease assessment. 
 
2.5.2          
Analysis of Key Parameters  
The comparison between treatment arms will be carried out using a two-sided test at a 1-sided alpha level of 5% 
unless otherwise specified.  All efficacy analyses will be presented by treatment arm. 
2.5.2.1 Progression Free Survival 
All randomized patients will also be included in the progression free survival (PFS) analysis. Kaplan-Meier 
curves for the distribution of PFS in each treatment arm will be displayed. The difference between survival 
distribution of the two treatment arms will be tested using the log-rank test stratified by:  ECOG PS (0,1 vs. 2), 
liver metastases (yes vs. no), lymph node metastases only (yes vs. no), hemoglobin (< 100 vs. ≥ 100) and 
interval from last platinum based chemotherapy (≤ 6 months vs. > 6 months). Estimate of hazard ratio (HR) and 
its 90% C.I. will be obtained from Cox regression stratified by the stratification factors except center. (Table 
10). 
 
Log-rank test will also be performed without adjusting those stratification factors.  
 
 
In addition, the effect of study centre and other potential prognostic factors will be assessed using Cox 
regression analysis. The Schoenfeld [Schoenfeld 1982] residual plots will be used to check the proportional 
hazard assumption. The 95% confidence intervals for the median survival will be computed using the method of 
Brookmeyer and Crowley. 
 
A table will be presented for the summary of types of progression by arm. For patients who did not progress, a 
table will be printed for the reasons for censoring, which includes receiving anti-cancer therapy for Urothelial 
carcinoma, prior to documentation of disease progression. (Table 11). 
 
Subgroup Analysis: The analysis of PFS will be presented for each level of stratification factors, median PFS, 
and its 95% C.I., estimate of HR and its 95% C.I., p-value from the interaction test below.  (Table 12) 
 
Cox regression model with interaction terms included to test homogeneity of treatment effect across the 
level of stratification factors (Exclude those with missing). 
Those factors are: ECOG PS (0,1 vs. 2), liver metastases (yes vs. no), lymph node metastases only (yes vs. no), 
hemoglobin (< 100 vs. ≥ 100) and interval from last platinum based chemotherapy (≤ 6 months vs. > 6 months). 


 
It should be pointed out that the main purpose for this section is to see if the treatment effects are homogeneous 
across the levels of each stratification factor. The sample size may not be large enough to detect a small or 
moderate difference in each subgroup.   
 
The anti-cancer therapy received after the progression will also be tabulated (Table 13). 
 
2.5.2.2 Overall survival  
All analysis for PFS will be performed for OS. And a table summarizes the death causes by arm.  
(Table 14-16). 
2.5.2.3 Clinical benefit response rate  
The Clinical benefit response rate for all evaluable patients will be calculated by treatment arm.  Cochran-
Mantel-Haenszel (CMH) test stratified for ECOG PS (0,1 vs. 2), liver metastases (yes vs. no), lymph node 
metastases only (yes vs. no), hemoglobin (< 100 vs. ≥ 100) and interval from last platinum based chemotherapy 
(≤ 6 months vs. > 6 months) will be used to test the difference between 2 treatment arms.  (Table 17). 
 
Multiple logistic regression was used to study the correlation between the response and the patients’ baseline 
factors (table 18). 
 
The Clinical benefit response rate by stratification factors are summarized in table 19. 
2.5.2.4 Objective response rates 
The same analysis for Clinical benefit response rate will be performed for ORR. (Table 20, 21). 
 2.5.2.5 Time to response 
The median of time to response and its 95% C.I. will be presented, and the estimated HR and its 95% C.I. and 
p-value from log-rank test. (Table 21). 
2.5.2.6 The duration of response 
For the patients who had achieved CR/PR during the study, the median duration of response and its 95% C.I. 
will be presented by treatment. (Table 22). 
2.6    Drug Exposure 
 
2.6.1 Definitions and Variables 
2.6.1.1 Duration of Study Therapy in months, cumulative dose 
Duration of study therapy (weeks) is defined as the time from the first date the patients took Nab-Paclitaxel / 
Paclitaxel to the date of final dose given. 
 
X 
Duration of study therapy (weeks) for all patients by treatment arms (Table 23): median, min and 
max; mean and STD.  
 
2.6.1.2   Cumulative dose, dose intensity and relative dose intensity of Nab-Paclitaxel / Paclitaxel 
The total of Nab-Paclitaxel / Paclitaxel doses taken by the patients is defined as the sum of Nab-Paclitaxel / 
Paclitaxel taken by patients during the duration of the study. 
 
Dose intensity is defined as the cumulative dose received divided by the duration of the study therapy in cycles. 
 


Relative dose intensity is defined as dose intensity divided by the dose prescribed for the duration of the study 
therapy (Nab-Paclitaxel 260mg/m2, Paclitaxel 175mg/m2 times the number of the cycles of the patient was on 
treatment). 
 
Χ 
 Total of Nab-paclitaxel /paclitaxel  doses (Table 23): median, min and max. 
X          Dose intensity per patient during the study (Table 23). 
   Χ   
 Relative dose intensity per patient during the study (Table 23). 
 
2.6.1.3     Dose reduction, interruption or discontinuation  
Nab-Paclitaxel / Paclitaxel dose may be adjusted (reduced, interrupted or discontinued) because of toxicities or 
other reasons.  The dose of a patient is considered to be reduced, interrupted or discontinued if there is a record 
in the reason for dose modification in Nab-Paclitaxel / Paclitaxel administration table in the treatment report 
form.  Specifically, the dose of a patient is considered to be reduced if there is a record in the Dose (mg) column 
in the table which is less than planned dose but greater than 0 mg; the dose of a patient is considered to be 
interrupted if there is at least one record in the Dose (mg) column on the drug table which is equal to 0. The 
drug is considered permanently discontinued if there are reasons for Nab-Paclitaxel / Paclitaxel was 
permanently stopped in the end of treatment form.   (Table 24) 
Χ 
Number of patients with at least one dose reduction, interruption during the study  
Χ 
Specify the primary reason for the dose reduction, interruption: % of patients with each reason 
(e.g., hematologic toxicity, administrative, etc.) 
Χ 
Number of patients whose dose was reduced at least once 
Χ 
Specify the primary reason for the dose reduction: % of patients with each reason (e.g., certain 
specific toxicity, administrative, etc.) 
Χ 
Specify secondary reason for dose reduction: % of patients with each reason (e.g., rash etc.) 
Χ 
Number of patients with at least one dose interruption 
Χ 
Specify reason for the dose interruption: % of patients with each reason (e.g., certain specific 
toxicity, administrative, etc.) 
Χ 
Specify secondary reason for dose interruption: % of patients with each reason (e.g., rash etc.) 
Χ 
Number of patients discontinued protocol treatment 
Χ 
Specify reasons for protocol treatment discontinuation: % of patients with each reason (e.g., 
progressive disease, intercurrent illness, etc.)  
 
2.6.2            
Analysis 
All variables will be summarized for all treated patients by treatment received.  
2.7  Safety  
2.7.1     
Definitions and variables 
2.7.1.1             Laboratory tests 
Analyses of laboratory data will include analyses of hematology and biochemistry tests.  The hematology data 
include Anemia, WBC, platelets, neutrophils and the biochemistry data include ALT (SGPT), total bilirubin, 
serum creatinine (Tables 25-26).  Laboratory results will be graded according to the CTC criteria version 4.0. 
 
All laboratory data collected at any time during the study for these tests will be included in the analyses of worst 
value on study and those collected during a specific cycle for these tests will be included in the analyses of 
worst value during that cycle. 
 
All tests specified above: 


          Χ CTC grade for worst value on-study (for hematology and biochemistry tests): %0, 1, 2, 3, 4 
           
 
2.7.1.2 Toxicity/adverse event/intercurrent illness 
The CTC version 4.0 will be used to summarize toxicities/adverse events/intercurrent illnesses.  Events will be 
displayed by primary term.  All toxicities/adverse events/intercurrent illnesses data collected during the trial 
will be included in the analyses of worst value on study, and data collected during a specific cycle will be 
included in the analyses of worst value during that cycle.   All the analyses will be repeated to include only the 
toxicities/adverse events/intercurrent illnesses which are drug related (The relation to protocol therapy higher 
than or equal to 3).  
Χ 
Any event during the study (Table 27): % yes 
Χ 
Worst severity per patient per primary term on study (Table 27) (analysis per cycle will also be 
performed, table xx): % CTC grade 1, 2, 3, 4, unknown 
Χ 
Toxicity/adverse event/intercurrent illness which are serious (reasons for seriousness in the 
serious adverse event table for electronic SAEs and toxicity table higher than or equal to 1), 
fatal only; life threatening; leading to hospitalization; results in significant disability or 
incapacity; congenital anomaly; required intervention/important medical event,  (Table 28). 
Χ 
Toxicity/adverse event/intercurrent illness that led to study drug discontinuation (Table 29) 
Χ 
Toxicity/adverse event/intercurrent illness that led to dose interruptions (Table 30) 
Χ 
Toxicity/adverse event/intercurrent illness that led to dose reduction (Table 31) 
            Deaths within 30 days from last treatment administration (Table 32) 
            Cause of death within 30 days from last treatment administration (Table 32).  
 
2.7.2           
Analysis 
All patients who received at least one dose of study medication will be included in the safety analyses. Top 5 
toxicities, and drug related grade 3 or higher will be compared using the Fisher’s exact test for comparison of 
the toxicity rates between 2 treatment arms.    
 
2.8     Concomitant medications, transfusion and hospitalization 
2.8.1           
Definition and Variables 
Concomitant medications are all other medications (other than study drugs) taken at any time on-study. 
Hospitalizations are those which occur at any time on-study.   
Χ 
Any Antiemetics per patient (Table 33): % yes, no.  
Χ 
Any Growth Factors and Blood Products per patient (Table 33): % yes, no 
Χ 
Any Bisphosphonates and Bone Targeted Agents per patient (Table 33): % yes, no 
Χ 
Any hospitalization per patient (Table 33): % yes, no, Duration: Median and range. 
 
 
 
 
2.8.2          
Analysis 
Supportive and concomitant medications and therapies will be displayed for all treated patients.  The data will 
be presented as shown in the table samples in Table 33. 
2.9 
Off- protocol therapies  
2.9.1    Definitions and Variables 
Χ 
Patients off- protocol therapies: Number and % of all randomized patients 
Χ 
Reason for going off- protocol therapies: Number and % of all randomized patients for each 
reason 


2.9.2      
Analysis 
Tables will be presented by treatment arm and for all patients (table 34). 
 
2.10 Quality of life 
 
General QoL domains were assessed using the EORTC-C15-PAL questionnaire. This self-administered 
questionnaire is a shortened version of widely used EORTC-QLQ-C30. It consists of 15 items. Pain, physical 
function, emotional function, fatigue, global health status/quality of life, nausea/vomiting, appetite, dyspnoea, 
constipation, and sleep are retained. Four scales were shortened without reducing measurement precision. The 
validity and reliability of this questionnaire have each been established.  
 
Since taxane-related peripheral neuropathy is an important symptom that adversely affects QoL in patients 
treated with either intervention, differences between arms in either the severity or duration of peripheral 
neuropathy would be important to detect. For this purpose, the FACT-Taxane questionnaire were added to the 
battery of Protocol Reported Outcomes (PROs). FACT-Taxane is a 16 item instrument that has been validated 
in patients with metastatic disease receiving taxane therapy, and has been shown to have excellent internal 
consistency, group validity, and responsiveness to change.  
 
 
2.10.1 Definitions and Variables 
2.10.1.1 
EORTC QLQ- C15-PAL 
EORTC QLQ-C15-PAL questionnaire is a short version of the QLQ-C30 for palliative care. The questionnaire 
includes four multi-item scales and six individual items. All items (except the global assessment, question no. 
15) were scaled from 1 (not at all) to 4 (very much), in which a higher score indicates greater distress in 
symptom scales while a higher score in functional scale indicates greater functional ability. Each scale will be 
converted to a score ranging from 0 to 100. 
 
If the number of unanswered questions in each domain is within a limit specified with the definition for each 
domain, the score is calculated as for function domains: 
Score=100-(((Total score for the answered questions/(no. of questions answered))-1)*100/3) 
And for symptom domains: 
Score = (((Total score for the answered questions/(no. of questions answered))-1)*100/3) 
Otherwise, the score will be recorded as “missing”.  For each single item, the score will be recorded as 
“missing” if the answer to this item is missing. 
 
Functional Domains/Symptoms items: 
 
X Physical functioning:  Questions: 1, 2, 3.  
 
Score=missing if number of above questions not answered is greater than 1;   
X Emotional functioning: Questions: 13, 14. 
                             Score=missing if number of above questions not answered is greater than 0; 
X Global: Question: 15 
 
Score = ((Answred score for the questions-1)*100/6. 
 
X Fatigue:  Questions: 7, 11 
                              Score=missing if number of above questions not answered is greater than 0; 
 
X Nausea and vomiting: 
 
Questions:9 
 
 
Score=missing if number of above questions not answered is greater than 0;  


X Pain: 
 
 
 
Questions: 5, 12 
 
 
Score=missing if number of above questions not answered is greater than 0. 
X 
Dyspnea: 
 
 
 
Question 4; 
Score=missing if the answer to the item is missing 
X 
Insomnia: 
 
 
 
Question 6; 
Score=missing if the answer to the item is missing 
X 
Appetite loss:  
 
 
Question 8; 
Score=missing if the answer to the item is missing 
X 
Constipation:  
 
 
Question 10; 
Score=missing if the answer to the item is missing. 
2.10.1.2 
The FACT-Taxane questionnaire 
FACT-Taxane is a 16 item instrument that has been validated in patients with metastatic disease receiving 
taxane therapy, and has been shown to have excellent internal consistency, group validity, and responsiveness to 
change 
 
Tax-subscale = ((The sum of 4 – item response score for all the answered items) / (no. of questions 
answered))*16 (Range 0 – 64).   
 
Score=missing if more than 8 items are missing 
2.10.2 Analysis 
All analyses on quality of life scores will be exploratory and will include all randomized patients with at least 1 
on study measurement besides the baseline evaluation. 
2.10.2.1 
Determination of Assessment Times 
The following will be the scheme to determining the time frame of a QOL assessment:  
1)  Baseline: Baseline evaluation is the QOL questionnaire collected closest, but prior to, the first day of 
starting study treatment/randomization; 
2) After completion of RT: If the QOL is assessed within 6 week of the date RT completion.  
3) Every 6 months FU evaluation, Within 2 months of the scheduled time points.  
4) At progression: If the QOL is assessed within 1 month when the progression is documented; 
 
2.10.2.2 
Calculation of Compliance Rates  
Three methods will be used to calculate the compliance rates of QOL assessment. The first two are based on the 
number of forms received out of respectively all eligible patients enrolled into the study and all patients who 
had baseline QOL assessments. The last one is calculated as the number of forms received out of the number of 
forms expected at each assessment point defined based on the following principles: 
1) At baseline: the number of forms expected is the total number of patients who are eligible for the study 
and required to fill out QOL questionnaires.  
2) At days 5 -7 of cycle 1 and 2, day 1 of cycle 4 and then day 1 of every 4 cycles thereafter: the number 
expected is the total number of patients who are eligible, had baseline QoL data and completed the cycle 
of treatment; 
3) At progression: the number expected is the total number of patients who are eligible, had baseline QoL 
data and has progressed; 
4)   At every 6 week visit FU period: the number expected at each assessment is the number of patients with 
baseline data minus the number of patients who have died or progressed during that and previous follow 
up period (Table 35). 
 


2.10.2.3 
Cross-sectional analysis 
The mean and standard deviation of QOL scores at baseline (Table 36) and mean and standard deviation of 
QOL change scores from baseline (Table 37) at each assessment time will be calculated.  Then Wilcoxon Rank-
Sum test is used to compare two treatment arms in terms of change in QOL score at each assessment time from 
baseline (see Table 36).  
 
2.10.2.4 
 
QOL response analysis 
QOL response is calculated as follows for a functional domain: A change score of 10 points from baseline was 
defined as clinically relevant. Patients were considered improved if reported a score 10-points or better than 
baseline at any time of QOL assessment. Conversely, patients were considered worsened if reported a score 
minus 10-points or worse than baseline at any time of QOL assessment without above specified 10-ponits 
improvement. Patients whose scores were between 10-point changes from baseline at every QOL assessment 
were considered as stable. In contrast to functional domains, for the determination of patient’s QOL response, 
classification of patients into improved and worsened categories is revered for symptom domains and single 
items. Chi-square test is then performed to compare the distributions of these three categories between two arms 
and follow with a trend test to see if patients one study treatment arm had higher proportions with better QoL 
responses. Note: For FACT-Taxane scale, we will use 6.5 instead of the 10 point in the response analysis.  
 


3. Tables 
Table 1:  Accrual by Center 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
Nab-Paclitaxel     
N = *** 
paclitaxel 
N = *** 
Total 
N = *** 
Center #1 
*** (**) 
*** (**) 
*** (**) 
Center #2 
*** (**) 
*** (**) 
*** (**) 
Center #3 
*** (**) 
*** (**) 
*** (**) 
... 
*** (**) 
*** (**) 
*** (**) 
 


 
Table 2:  Accrual by Stratification Factor at Randomization 
 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
Nab- Paclitaxel 
N = *** 
Paclitaxel  
N=*** 
Total 
N = *** 
 ECOG PS 
 
 
 
 
0, 1 
** (**) 
** (**) 
** (**) 
 
2 
** (**) 
** (**) 
** (**) 
 
 
 
 
 liver metastases 
 
 
 
No 
** (**) 
** (**) 
** (**) 
Yes 
** (**) 
** (**) 
** (**) 
hemoglobin 
 
< 100 
 
≥100 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
lymph node metastase
only 
yes 
 
no 
 
 
** (**) 
** (**) 
 
 
** (**) 
** (**) 
 
 
** (**) 
** (**) 
Interval from last 
platinum based 
chemotherapy  
          ≤ 6 months 
          > 6 months 
 
 
** (**) 
** (**) 
 
 
** (**) 
** (**) 
 
 
** (**) 
** (**) 
 
 
Source:  Centralized Randomization File 
 
 


Table 3:  Treatment as Randomized Versus as Treated at Cycle 1 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
Randomized Arm 
 
NAB-PACLITAX
N=*** 
Paclitaxel  
N=*** 
Total 
N=*** 
Treatment Received 
 
 
 
         NAB-PACLITAXEL  
*** (**) 
*** (**) 
*** (**) 
         Paclitaxel  
*** (**) 
*** (**) 
*** (**) 
         Not treated 
*** (**) 
*** (**) 
*** (**) 
 
 
Table 4:  Discrepancies between Stratification Level as Randomized and at Baseline 
 
Data set:  All Randomized Patients 
 
Number of patients (%) 
 
NAB-PACLITAXE
N=*** 
Paclitaxel  
N=*** 
Total 
N=*** 
Any difference 
*** (**) 
*** (**) 
*** (**) 
At baseline 
As Randomized 
As Randomized
As Randomized 
 ECOG PS 
0, 1 
2 
0, 1 
2 
0, 1 
2 
 
0, 1 
** 
** 
** 
** 
** 
** 
 
2 
** 
** 
** 
** 
** 
** 
hemoglobin 
< 100 ≥ 100 
< 100 
≥ 100 
< 100 
≥ 100 
<100 
** 
** 
** 
** 
** 
** 
≥100 
** 
** 
** 
** 
** 
** 
liver metastases 
Yes 
No 
Yes 
No 
Yes 
No 
 
Yes 
** 
** 
** 
** 
** 
** 
 
No 
** 
** 
** 
** 
** 
** 
lymph node meta only 
Yes 
No 
Yes 
No 
Yes 
No 
 
Yes 
** 
** 
** 
** 
** 
** 
 
No 
** 
** 
** 
** 
** 
** 
interval from last platinu
based chemotherapy 
< 6M 
≥ 6M
< 6M
≥6M
<6M 
≥6M 
 
≤ 6 Months 
** 
** 
** 
** 
** 
** 
 
> 6 months 
** 
** 
** 
** 
** 
** 
 


Table 5:  Eligibility, Reasons for Ineligibility and Major Protocol Violations 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
Nab- Paclitaxel 
N=*** 
Paclitaxel 
N=*** 
Total 
N=*** 
 
 
 
 
Eligible 
*** (**) 
*** (**) 
*** (**) 
Not Eligible 
*** (**) 
*** (**) 
*** (**) 
 
 
 
 
Reason for ineligibility  
 
 
 
 
<Reason 1> 
** 
** 
** 
 
<Reason 2> 
** 
** 
** 
 
... 
 
** 
** 
** 
Major protocol violation 
 
<violation 1> 
 
<violation 2> 
 
… 
 
** 
** 
** 
 
** 
** 
** 
 
** 
** 
** 
 
Table 6:  Month of Last Follow-up for all Patients and min and max FU for alive patients 
 
Data set:  All Randomized Patients 
 
Number of patients 
 
NAB-PACLITAXEL
Paclitaxel  
Total 
Number of patients alive
*** 
*** 
*** 
Follow Up time 
Median, min, Max. 
Median, min, Max. Median, min, Max. 
 


Table 7:  Pretreatment Characteristics at Baseline 
 
Data set: All Randomized Patients
Number of patients (%)
 
Nab- Paclitaxel 
N=*** 
Paclitaxel  
N=*** 
Total 
N=*** 
Gender
    Female 
** (**) 
** (**) 
** (**) 
     Male 
** (**) 
** (**) 
** (**) 
Race 
 
 
 
    White 
** (**) 
** (**) 
** (**) 
Black
** (**)
** (**)
** (**)
    .... 
** (**) 
** (**) 
** (**) 
 
 
 
 
Age (years) 
 
 
 
N 
Median 
Min - Max 
** 
** 
** - ** 
** 
** 
** - ** 
** 
** 
** - ** 
      
≤ 65  
> 65 
        
       ** (**) 
** (**) 
 
** (**) 
** (**) 
 
** (**) 
** (**) 
 
 
 
 
Prior IO  
 
 
 
No
** (**)
** (**)
** (**)
     Yes 
** (**) 
** (**) 
** (**) 
 
  


Table 8:  Baseline Signs and Symptoms 
 
 
Data set:  All Randomized Patients (NAB-PACLITAXEL     Arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade
 
NR
1 
2 
3 
4 
 
Patients with any 
sign/symptom at baseline 
** (*
** (**
** (**
** (**
** (**
** (**) 
Patients with particular sig
symptom, within body 
system:  
Body System 1(1) 
Event 1 
Event 2 
Event 3 
...  
Body System 2(1) 
Event 1  
...  
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a body system 
 
 
NOTE:  Same table to be made for Paclitaxel  Arm 
 


Table 8:  Baseline Hematology/Biochemistry 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
 
 
NAB-PACLITAX
N = *** 
Paclitaxel 
N = *** 
Total 
N=*** 
 
 
 
 
WBC 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
Anemia 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
Neutrophils 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
Platelet 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 
Serum creatinine 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
 
 
 


bilirubin 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
ALT (SGPT) 
 
 
 
 
Grade 0 
** (**) 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
** (**) 
 
Not reported (1) 
** (**) 
** (**) 
** (**) 
 
(1) Not done  
 
Table 10:  Log rank and Cox Regression Model for Progression Free Survival 
 
 
Data set:  All Randomized Patients  
 
Univariate Analysis(1) 
 
Multivariate Analysis(2)
Treatment Arm/
Prognostic Factors
Baseline 
Median
Survival
(Months
Hazard 
Ratio(4) 
(95% CI) 
Log-ran
p-vlaue
Hazard 
Ratio(4) 
(95% C.I.
P-vlaue 
from Cox
regression
 
 
 
 
 
 
Treatment arm 
 
 
†0.***
 
0.*** 
NAB-PACLITAXEL  
**.** 
**.** 
 
**.**  
 
Paclitaxel  
**.** 
(**.**,**.**
 
(**.**,**.*
 
 
 
 
 
 
 
Prognostic factor 1 
 
 
0.***
 
0.*** 
 
Level 1 
**.** 
NC (3) 
 
**.**  
 
Level 2 
**.** 
 
 
(**.**,**.*
 
 
 
 
 
 
 
Prognostic factor 2 
 
 
0.***
 
0.*** 
 
Level 1 
**.** 
NC 
 
**.**  
 
Level 2 
**.** 
 
 
(**.**,**.*
 
 
 
 
 
 
 
Prognostic factor 3 
 
 
0.***
 
0.*** 
 
Level 1 
**.** 
NC 
 
**.**  
 
Level 2 
**.** 
 
 
(**.**,**.*
 
 
 
 
 
 
 
 
… 
 
 
0.***
 
0.*** 
 
… 
**.** 
NC 
 
**.**  
 
… 
**.** 
 
 
(**.**,**.*
 
(1) Stratified 
(2) Stratified Cox regression with all factors included 
(3) NC = not computed 
(4) Hazard ratio of first category over second category 


Figure 1: K-M curves of PFS by treatment arm 
Table 11 Progression Summary 
 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
NAB-PACLITAXE
N=*** 
Paclitaxel  
N=*** 
 
 
 
Patients who progressed 
*** (**) 
*** (**) 
 
 
 
 
Progression on study 
** 
** 
 
Progression during follow-up 
** 
** 
 
Death (without documented 
  
progression) 
** 
** 
 
 
 
Patients who were censored 
 
*** (**) 
*** (**) 
   Reason Censored 
 
Received anti-cancer therapy before
documented progression: 
 
 
 
  Chemotherapy 
** 
** 
 
   Radiotherapy 
** 
** 
 
  Hormonal therapy 
** 
** 
 
   Immunotherarpy 
** 
** 
 
  .... 
** 
** 
 
 
 
 
 
Lost to follow-up 
 
** 
 
** 
 
 
Not progressed 
 
** 
 
** 
 
 
 
 


 
Table 12:  Progression free Survival by Subsets 
 
 
Data set:  All Randomized Patients 
 
  
 
Factors 
 
 
Value 
Nab- Paclitaxel 
Paclitaxel  
 
 
 
N 
Median 
Survival 
95% C.I. 
 
N 
Median 
Survival 
95% C.I. 
Hazard Ratio(1) 
95% C.I. 
Int-p-value 
 
 
 
 
 
 
 
 
ECOG PS 
0, 1 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.*** 
 
2 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
 
 
 
 
 
 
 
 
liver 
metastases 
Yes 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.** 
 
No 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
hemoglobin 
<100 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.** 
 
>100 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
lymph node 
metastases 
Yes 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.** 
 
No 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
lymph interval from 
last platinum based 
chemotherapy 
≤ 6M 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
 
>6M 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
 (1) Nab- Paclitaxel over Paclitaxel  hazard ratio (Unstratified) 
         0.** 


Table 13:  Anti-Cancer Therapy Received After Progression 
 
 
Data set:  All Randomized patients 
 
 
Number of patients (%) 
 
NAB-PACLITAX
N=*** 
Paclitaxel  
N =*** 
Number of patients with any follow-up therapy 
*** (**) 
*** (**) 
 
 
 
   Chemotherapy (1) 
   EGFR inhabitor (1) 
   Radiotherapy (1) 
   Hormonal therapy (1) 
   Immunotherapy (1) 
   Other (1) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
*** (**) 
 
(1) Patients could have more than one type of  therapy. 
 
 
 
Figure 2: K-M curves of OS by treatment arm 


 
Table 14:  Log rank and Cox Regression Model for Overall Survival 
 
 
Data set:  All Randomized Patients  
 
Univariate Analysis(1) 
 
Multivariate Analysis(2)
Treatment Arm/
Prognostic Factors
Baseline 
Median
Survival
(Months
Hazard 
Ratio(4) 
(95% CI) 
Log-ran
p-vlaue
Hazard 
Ratio(4) 
(95% C.I.
P-vlaue 
from Cox
regression
 
 
 
 
 
 
Treatment arm 
 
 
†0.***
 
0.*** 
NAB-PACLITAXEL  
**.** 
**.** 
 
**.**  
 
Paclitaxel  
**.** 
(**.**,**.**
 
(**.**,**.*
 
 
 
 
 
 
 
Prognostic factor 1 
 
 
0.***
 
0.*** 
 
Level 1 
**.** 
NC (3) 
 
**.**  
 
Level 2 
**.** 
 
 
(**.**,**.*
 
 
 
 
 
 
 
Prognostic factor 2 
 
 
0.***
 
0.*** 
 
Level 1 
**.** 
NC 
 
**.**  
 
Level 2 
**.** 
 
 
(**.**,**.*
 
 
 
 
 
 
 
Prognostic factor 3 
 
 
0.***
 
0.*** 
 
Level 1 
**.** 
NC 
 
**.**  
 
Level 2 
**.** 
 
 
(**.**,**.*
 
 
 
 
 
 
 
 
… 
 
 
0.***
 
0.*** 
 
… 
**.** 
NC 
 
**.**  
 
… 
**.** 
 
 
(**.**,**.*
 
(1) Stratified 
(2) Stratified Cox regression with all factors included 
(3) NC = not computed 
(4) Hazard ratio of first category over second category 
 


 
Table 15 Death Summary 
 
 
Data set:  All Randomized Patients 
 
Number of Patients (%) 
NAB-PACLITAXE
N=*** 
Paclitaxel  
N=*** 
 
 
 
Patients who died 
*** (**) 
*** (**) 
 
Death Causes 
 
 
            Disease 
** 
** 
 
Disease/treatment complication 
** 
** 
 
Others 
 
** 
** 
Table 16:  Overall Survival by Subsets 
 
 
Data set:  All Randomized Patients 
 
  
 
Factors 
 
 
Value 
Nab- Paclitaxel 
Paclitaxel  
 
 
 
N 
Median 
Survival 
95% C.I. 
 
N 
Median 
Survival 
95% C.I. 
Hazard Ratio(1) 
95% C.I. 
Int-p-value 
 
 
 
 
 
 
 
 
ECOG PS 
0, 1 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.*** 
 
2 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
 
 
 
 
 
 
 
 
liver 
metastases 
Yes 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.** 
 
No 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
hemoglobin 
<100 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.** 
 
>100 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
lymph node 
metastases 
Yes 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
0.** 
 
No 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
lymph interval from 
last platinum based 
chemotherapy 
≤ 6M 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
 
> 6M 
** 
*.** 
(*.**,*.**) 
** 
*.** 
(*.**,*.**) 
*.** 
(*.**,*.**) 
 
 (1) Nab- Paclitaxel over Paclitaxel  hazard ratio (Unstratified) 
         0.** 


Table 17:  Clinical benefit response rate 
Data set:  All Randomized  Patients 
 
Number of Patients (%)* 
N=*** 
NAB-PACLITAXEL
N=*** 
Paclitaxel  
N=*** 
 
 
 
Patients with at least one target lesion** 
 
N=*** 
 
N=*** 
 
 
Complete response (CR) 
 
** (**) 
 
** (**) 
 
Partial response (PR) 
 
** (**) 
 
** (**) 
 
Stable disease (SD) 
 
** (**) 
 
** (**) 
 
Progressive disease (PD) 
 
** (**) 
 
** (**) 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
 
** (**) 
** 
** 
... 
 
** (**) 
** 
** 
.... 
 
 
 
 
Patients with no target lesions*** 
 
 
N=*** 
 
N=*** 
 
Complete response (CR) 
 
Stable Disease (SD) 
 
Progressive disease (PD) 
 
** 
 
** 
 
** 
 
** 
 
** 
 
** 
 
Inevaluable for response (IN) 
<Reason 1> 
<Reason 2> 
.... 
 
** 
** 
** 
... 
 
** 
** 
** 
.... 
 
 
 
 
 
*   percentages are calculated out of the number of  patients in each category  
** only patients with at least one target lesion are evaluable as defined by RECIST 
*** patients with non-measurable disease only were followed for complete response, and disease progression. 
Patients who were assessed but did not meet the definition of CR or PD were recorded as SD. 
 


Table 18:  Cochran Mantel Haenszel and Logistic Regression Model for Clinical benefit response rate 
 
Data set:  All Randomized Patients 
 
Univariate Analysis (1) 
Multivariate Analysis (2) 
 
Treatment/ Prognostic Facto
Odds Ratio 
(95%CI) 
CMH 
p-vlaue 
Odds Ratio
(95% C.I.
p-value 
from logisti
regression 
 
 
 
 
 
Treatment arm 
 
0.*** 
 
0.*** 
NAB-PACLITAXEL    : 
Paclitaxel  
**.** 
 
**.** 
 
 
 
(**.**,**.*
 
(**.**,**.*
 
 
 
 
 
 
Prognostic factor 1 
 
0.*** 
 
0.*** 
 
Level 1: level 2 
NC (3) 
 
**.** 
 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
Prognostic factor 2 
 
0.*** 
 
0.*** 
 
Level 1: level 2 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
Prognostic factor 3 
 
0.*** 
 
0.*** 
 
Level 1: level 2 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
 
… 
 
0.*** 
 
0.*** 
 
… 
NC 
 
**.** 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
(1) Stratified 
(2) Stratified Logistic regression, all factors included 
(3) NC = not computed 
(4) Odds ratio of first category over second category 
 
 


 
Table 19:  Clinical benefit response rate According to Baseline Stratification Factors 
 
 
 
Data set:  All Randomized Patients 
 
 
Number of Responses/Number of Patients (%) 
Nab-Paclitaxel  
       N=*** 
Paclitaxel  
N=*** 
Int-P-value 
 
 
 
 
 
 
 
 
ECOG performance status 
 
 
0.** 
 
0+1 
**/** (**) 
**/** (**) 
 
 
2+ 
**/** (**) 
**/** (**) 
 
 
liver metastases 
 
 
 
 
Yes 
**/** (**) 
**/** (**) 
0.** 
 
No 
**/** (**) 
**/** (**) 
 
 
 
 
 
 
 
 
 
lymph node metastases only 
 
 
 
 
Yes 
**/** (**) 
**/** (**) 
0.** 
 
No 
**/** (**) 
**/** (**) 
 
 
 
 
 
 
hemoglobin 
 
 
 
 
< 100 
**/** (**) 
**/** (**) 
0.** 
 
≥  100 
**/** (**) 
**/** (**) 
 
interval from last platinum based chemotherapy 
 
 
 
 
≤ 6 M 
**/** (**) 
**/** (**) 
0.** 
 
>  6M 
**/** (**) 
**/** (**) 
 
 
 
 
 
 
 
 
 
 


Table 20:  Cochran Mantel Haenszel and Logistic Regression Model for best response rate 
 
Data set:  All Randomized Patients 
 
Univariate Analysis (1) 
Multivariate Analysis (2) 
 
Treatment/ Prognostic Facto
Odds Ratio 
(95%CI) 
CMH 
p-vlaue 
Odds Ratio
(95% C.I.
p-value 
from logisti
regression 
 
 
 
 
 
Treatment arm 
 
0.*** 
 
0.*** 
NAB-PACLITAXEL    : 
Paclitaxel  
**.** 
 
**.** 
 
 
 
(**.**,**.*
 
(**.**,**.*
 
 
 
 
 
 
Prognostic factor 1 
 
0.*** 
 
0.*** 
 
Level 1: level 2 
NC (3) 
 
**.** 
 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
Prognostic factor 2 
 
0.*** 
 
0.*** 
 
Level 1: level 2 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
Prognostic factor 3 
 
0.*** 
 
0.*** 
 
Level 1: level 2 
NC 
 
**.** 
 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
 
… 
 
0.*** 
 
0.*** 
 
… 
NC 
 
**.** 
 
 
 
 
(**.**,**.*
 
 
 
 
 
 
(1) Stratified 
(2) Stratified Logistic regression, all factors included 
(3) NC = not computed 
(4) Odds ratio of first category over second category 
 
 


 
Table 21:  Response rate According to Baseline Stratification Factors 
 
 
 
Data set:  All Randomized Patients 
 
 
Number of Responses/Number of Patients (%) 
Nab-Paclitaxel  
       N=*** 
Paclitaxel  
N=*** 
Int-P-value 
 
 
 
 
 
 
 
 
ECOG performance status 
 
 
0.** 
 
0+1 
**/** (**) 
**/** (**) 
 
 
2+ 
**/** (**) 
**/** (**) 
 
 
liver metastases 
 
 
 
 
Yes 
**/** (**) 
**/** (**) 
0.** 
 
No 
**/** (**) 
**/** (**) 
 
 
 
 
 
 
 
 
 
lymph node metastases only 
 
 
 
 
Yes 
**/** (**) 
**/** (**) 
0.** 
 
No 
**/** (**) 
**/** (**) 
 
 
 
 
 
 
hemoglobin 
 
 
 
 
< 100 
**/** (**) 
**/** (**) 
0.** 
 
≥  100 
**/** (**) 
**/** (**) 
 
interval from last platinum based chemotherapy 
 
 
 
 
≤6 M 
**/** (**) 
**/** (**) 
0.** 
 
>  6M 
**/** (**) 
**/** (**) 
 
 
 
 
 
 
 
Table 21: Time to response 
 
 
 
 
 
Data set:  All Randomized Patients  
 
Univariate Analysis(1) 
 
Treatment Arm 
 
Median  
TTR 
(Months) 
(95% CI) 
Hazard 
Ratio(4) 
(95% CI) 
Log-rank 
p-vlaue 
 
 
 
 
Treatment arm 
 
 
†0.*** 
NAB-PACLITAXEL     
**.** 
(**.**,**.**) 
**.** 
 
 
Paclitaxel  
**.** 
(**.**,**.**) 
(**.**,**.**) 
 
 


Table 22:  Duration of Response 
 
 
Data set:  All Randomized Patients with a Response of CR or PR 
NAB-PACLITAXEL     
Paclitaxel  
N 
Median 
(months) 
(95% CI) 
N 
Median 
(months) 
(95% CI) 
Duration of Overall 
response (CR+PR) 
*** 
**.** 
(**.**, **.**) 
*** 
**.** 
(**.**, **.**) 
Duration of Complete 
response (CR)  
*** 
**.** 
(**.**, **.**) 
*** 
**.** 
(**.**, **.**) 
 
NOTE:  Same table to be made based on all response evaluable patients 
Table 23: Total treatment Duration and dose of  Nab-Paclitaxel /Paclitaxel  
 
Data Set: All Treated Patients  
Treatment arm 
Drug 
NAB-PACLITAXEL           Paclitaxel  
Duration in weeks: 
 
 
 
N 
*** 
*** 
 
Median  
* 
* 
 
Min – Max 
* - * 
* - * 
           Mean (STD) 
**(**) 
**(**) 
 
 
 
Total dose: 
 
 
 
N 
*** 
*** 
 
Median  
* 
* 
 
Min – Max 
* - * 
* - * 
           Mean (STD) 
**(**) 
**(**) 
Dose intensity 
 
          Median 
          Mean (STD) 
          Min – Max 
 
 
*** 
*** (**) 
***-*** 
 
 
*** 
***(**) 
***-*** 
Relative dose intensity 
 
         Median 
         Mean (STD) 
         Min – Max  
          
         ≥ 90% (n and %) 
         80%-90% (n and %) 
         <80% (n and %) 
 
 
*** 
***(**) 
***-*** 
 
** (**) 
** (**) 
** (**) 
 
 
*** 
***(**) 
***-*** 
 
** (**) 
** (**) 
** (**) 
 


Table 24 : Dose Reduction, Interruption or Discontinuation 
 
 
Data Set: All Treated Patients  
 
Number of patients (%) 
 
Nab-Paclitaxel (N=***) 
Paclitaxel  (N=***) 
 
At least one dose reduction, 
 
interruption or 
  
discontinuation 
 
** (**) 
 
** (**) 
Reason for dose reduction, 
  
interruption or 
 
discontinuation: 
 
 
<reason 1> 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
 
... 
** (**) 
** (**) 
 
 
 
 
At least one dose reduction  
 
** (**) 
 
** (**) 
Reason for dose reduction: 
 
 
<reason 1> 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
 
... 
** (**) 
** (**) 
 
 
 
 
At least one dose interruption
 
** (**) 
 
** (**) 
Reason for dose interruption:
 
 
<reason 1> 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
 
... 
** (**) 
** (**) 
 
Protocol treatment 
  
discontinuation  
 
** (**) 
 
** (**) 
Reason for discontinuation: 
 
 
<reason 1> 
** (**) 
** (**) 
 
<reason 2> 
** (**) 
** (**) 
 
... 
 
** (**) 
** (**) 
 
 


 
Table 25:  Hematology: Worst Ever Grade per Patient on Study 
 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
NAB-PACLITAXEL
Paclitaxel  
WBC  
 
 
 
Number of patients 
**  
**  
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Platelets  
 
 
 
Number of patients 
**  
**  
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Neutrophils 
 
 
 
Number of patients 
**  
**  
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Anemia 
 
 
 
Number of patients 
**  
**  
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
 
Similar tables for Toxicities occurred at each cycle for the first 4 cycle of treatment.   


Table 26:  Biochemistry:  Worst Grade per Patient over Study 
 
Data set:  All Treated Patients 
 
Number of patients (%) 
 
NAB-PACLITAXEL
Paclitaxel  
 ALT (SGPT) 
 
 
 
Number of patients 
**  
**  
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Total bilirubin 
 
 
 
Number of patients 
**  
**  
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
Creatinine 
 
 
 
Number of patients 
**  
**  
 
Grade 0 
** (**) 
** (**) 
 
Grade 1 
** (**) 
** (**) 
 
Grade 2 
** (**) 
** (**) 
 
Grade 3 
** (**) 
** (**) 
 
Grade 4 
** (**) 
** (**) 
 
 
 
 (2) Greater than upper normal limit 
NOTE: Patients can have more than one category (low and/or high) 
 


 
Table 27:  Toxicity/Adverse Events/Intercurrent Illness (worst ever over the study) 
 
 
Data set:  All Treated Patients (NAB-PACLITAXEL     Arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
NR 
1 
2 
3 
4 
 
Patients with any AE 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE within category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE: In Paclitaxel  Arm, the same type of table will be made.   Same type of tables which include only the 
toxicities/adverse events/intercurrent illnesses which are drug related will be made for both NAB-
PACLITAXEL    and Paclitaxel  arms.     
 


Table 28:  Worst Ever Toxicities/Adverse Event/Intercurrent Illness which are Serious, Fatal Only, 
Leading to Hospitalization 
 
Data set:  All Treated Patients (NAB-PACLITAXEL     Arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
NR 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
Patients with serious AE within 
category 
 
Category 1(1) 
Event 1 
...  
 
Category 2(1) 
Event 1  
...  
 
Patients with fatal AE within categ
 
Category 1(1) 
Event 1 
...  
 
Category 2(1) 
Event 1  
...  
 
Patients with AE leading to 
hospitalization within category 
 
Category 1(1) 
Event 1 
...  
 
Category 2(1) 
Event 1  
...  
 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE: In Paclitaxel  Arm, the same type of table will be made.   Same type of tables which include only the 
toxicities/adverse events/intercurrent illnesses which are drug related will be made for both NAB-
PACLITAXEL     and Paclitaxel  arms.     
 


Table 29:  Worst Ever Toxicity/Adverse Event/Intercurrent Illness Led to Dose Discontinuation 
 
 
 
Data set:  All Treated Patients (NAB-PACLITAXEL    Arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any grade 
 
NR 
1 
2 
3 
4 
 
Patients with any AE led to dose
discontinuation 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE led to dose 
discontinuation within category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE: In Paclitaxel  Arm, the same type of table will be made.   Same type of tables which include only the 
toxicities/adverse events/intercurrent illnesses which are drug related will be made for both NAB-
PACLITAXEL    and Paclitaxel  arms.     
 


Table 30:  Worst Ever Toxicity/Adverse Event/Intercurrent Illness Led to Dose Interruption 
  
 
Data set:  All Treated Patients (NAB-PACLITAXEL    Arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any gra
 
NR 
1 
2 
3 
4 
 
Patients with any AE led to d
interruption 
** (**) ** (**) 
** (**) 
** (**) ** (**) 
** (**) 
Patients with AE led to dose 
interruption within category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE: In Paclitaxel  Arm, the same type of table will be made.   Same type of tables which include only the 
toxicities/adverse events/intercurrent illnesses which are drug related will be made for both NAB-
PACLITAXEL    and Paclitaxel  arms.     
 


Table 31:  Worst Ever Toxicity/Adverse Event/Intercurrent Illness Led to Dose Reduction 
  
 
Data set:  All Treated Patients (NAB-PACLITAXEL    Arm) 
 
Number of patients (%) 
N=*** 
 
Worst grade 
Any gra
 
NR 
1 
2 
3 
4 
 
Patients with any AE led to dose 
reduction 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
** (**) 
Patients with AE led to dose reduct
within category 
 
Category 1(1) 
Event 1 
Event 2 
Event 3 
...  
 
Category 2(1) 
Event 1  
...  
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
 
 
**(**) 
**(**) 
**(**) 
**(**) 
**(**) 
 
**(**) 
**(**) 
**(**) 
(1) Patients may have more than one event within a category. 
 
NOTE: In Paclitaxel  Arm, the same type of table will be made.   Same type of tables which include only the 
toxicities/adverse events/intercurrent illnesses which are drug related will be made for both NAB-
PACLITAXEL    and Paclitaxel  arms.     
Table 32:  Deaths on Study within 30 Days 
 
Data set:  All Treated Patients 
 
Number of Patients (%) 
 
Nab- Paclitaxel 
  N=*** 
Paclitaxel 
N=*** 
Number of  Patients who died within 30 days of last treatment  
** (**) 
** (**) 
 
 
 
Cause of Death 
 
 
 
Urothelial carcinoma (UC) 
** 
** 
 
Toxicity from protocol treatment 
** 
** 
 
UC + Toxicity from Protocol Treatment complication 
** 
** 
 
Non-protocol Treatment Complication 
** 
** 
 
UC + Non-protocol Treatment Complication 
** 
** 
 
Other Primary Malignancy 
** 
** 
 
Other Condition or Circumstance 
** 
** 
 


 
Table 33:  Summary of Supportive and Concomitant Medications and Therapy, Transfusion and 
hospitalization 
 
Data Set: All Treated Patients 
 
 
Number of patients (%) 
 
Nab- 
Paclitaxel  
(n = ***) 
Paclitaxel  
(n = ***) 
TOTAL 
(n = ***) 
 
Any Antiemetics 
 
Any Growth Factors & blood 
transfusion 
 
Any Bisphosphonates and 
Bone Targeted Agents 
 
Any hospitalization 
 
Days of hospitalization 
 
Median 
 
Range 
 
*** 
 
 
*** 
 
 
*** 
 
*** 
 
 
** 
**-**
 
(**) 
 
 
(**) 
 
 
(**) 
 
(**) 
 
*** 
 
 
*** 
 
 
*** 
 
*** 
 
 
** 
**-** 
 
(**) 
 
 
(**) 
 
 
(**) 
 
(**) 
 
*** 
 
 
*** 
 
 
*** 
 
*** 
 
 
** 
**-** 
 
(**) 
 
 
(**) 
 
 
(**) 
 
(**) 
 
 
 
 
 
 
 
 
* Patients may have received more than one type of concomitant medication 
 
 
 


 
Table 34:  Reason Off-protocol Therapy 
 
 
 
 
Number of patients (%) 
 
NAB-
PACLITAXEL 
(n = ***) 
Paclitaxel  
(n = ***) 
TOTAL 
(n = ***) 
Number (%) patients off study ** 
(**) 
** 
(**) 
** 
(**) 
Reasons off study 
 
 
 
 
 
 
Progressive disease 
** 
(**) 
** 
(**) 
** 
(**) 
Symptomatic progression ** 
(**) 
** 
(**) 
** 
(**) 
Intercurrent disease 
** 
(**) 
** 
(**) 
** 
(**) 
Toxicity to protocol  
 
treatment 
** 
(**) 
** 
(**) 
** 
(**) 
Death 
** 
(**) 
** 
(**) 
** 
(**) 
Other 
** 
(**) 
** 
(**) 
** 
(**) 
Unknown 
** 
(**) 
** 
(**) 
** 
(**) 
Patient refusal 
** 
(**) 
** 
(**) 
** 
(**) 
 
 
 
Table 35:  Compliance (Received/Expected) with QOL Assessment by Treatment Arm 
 
                             NAB-PACLITAXEL                                       Paclitaxel  
   
Period         Expected     Received (%)       Expected    Received (%) 
 
Baseline 
*** 
*** (**.*) 
*** 
*** (**.*) 
Cycle1 
*** 
*** (**.*) 
*** 
*** (**.*) 
Cycle2 
*** 
*** (**.*) 
*** 
*** (**.*) 
… 
*** 
*** (**.*) 
*** 
*** (**.*) 
At progression 
*** 
*** (**.*) 
*** 
*** (**.*) 
6 week FU 1 
*** 
*** (**.*) 
*** 
***  (**.*) 
6 week FU 2 
*** 
*** (**.*) 
*** 
*** (**.*) 
… 
*** 
*** (**.*) 
*** 
*** (**.*) 
 


  
Table 36:  Baseline Score for Each Domain/item 
 
 
  Domain/item                        NAB-PACLITAXEL           Paclitaxel  
 
  Physical                N                    ***                *** 
                          MEAN                 **.**              **.** 
                          STD DEV              **.**              **.** 
 
  Emotional               N                    ***                ***  
                          MEAN                 **.**              **.** 
                          STD DEV              **.**              **.** 
 
  …                       N                    ***                *** 
                          MEAN                 **.**              **.** 
                          STD DEV              **.**              **.** 
 
 
 
Table 37:  Mean QOL Change Scores from Baseline for each Domain/item at Each Assessment Time 
 
Assessment 
                           NAB-
PACLITAXEL     
 
      N                    Mean (SD) 
                   Paclitaxel  
 
    N              Mean (SD) 
P value* 
Cycle1 
*** 
**.** (**.**) 
*** 
**.** (**.**) 
0.** 
Cycle2 
*** 
**.** (**.**) 
*** 
**.** (**.**) 
0.** 
… 
*** 
**.** (**.**) 
*** 
**.** (**.**) 
0.** 
Progression 
*** 
**.** (**.**) 
*** 
**.** (**.**) 
0.** 
6 week FU 1 
*** 
**.** (**.**) 
*** 
**.** (**.**) 
0.** 
6 week FU 2 
………. 
*** 
**.** (**.**) 
*** 
**.** (**.**) 
0.** 
 
*Wilcoxon rank sum test. 
 
(There will be one table for each domain/item). 
 


Table 38:  Results for QOL Response Analyses 
 
 
Domain 
Nab- Paclitaxel 
Improved     Stable    Worsen 
N (%) 
Paclitaxel  
Improved     Stable    Worsen 
N (%) 
 
P-value 
(Chi-
square 
test) 
 
p-value 
(MH 
trend 
test) 
EORTC QLQ-C15-PAL 
 
Physical 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Emotional 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Global 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Pain 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Fatigue 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Nausea 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Dyspnea 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Insomnia 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Appetite 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
Constipation 
***(**) 
***(**) 
***(**) ***(**) 
***(**) 
***(**) 
.** 
.** 
 
FACT-Taxane 
 
 
***(**) 
***(**) 
***(**) ***(**) ***(**) 
***(**) 
.** 
.**