Conditions: Childhood Choroid Plexus Tumor Childhood Ependymoblastoma Childhood Grade III Meningioma Childhood High-grade Cerebellar Astrocytoma Childhood High-grade Cerebral Astrocytoma Childhood Medulloepithelioma Recurrent Childhood Anaplastic Astrocytoma Recurrent Childhood Anaplastic Oligoastrocytoma Recurrent Childhood Anaplastic Oligodendroglioma Recurrent Childhood Brain Stem Glioma Recurrent Childhood Cerebellar Astrocytoma Recurrent Childhood Cerebral Astrocytoma Recurrent Childhood Giant Cell Glioblastoma Recurrent Childhood Glioblastoma Recurrent Childhood Gliomatosis Cerebri Recurrent Childhood Gliosarcoma Recurrent Childhood Medulloblastoma Recurrent Childhood Pineoblastoma Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
This phase I trial studies the side effects and best dose of palbociclib isethionate in treating younger patients with central nervous system tumors that have grown, come back, or not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD)/phase II recommended dose and describe toxicities related to PD-0332991 (palbociclib isethionate) in children with retinoblastoma protein 1 (Rb1) positive recurrent, progressive or refractory primary central nervous system (CNS) tumors.

II. To determine plasma pharmacokinetics of PD-0332991 in children with Rb1positive recurrent, progressive or refractory primary CNS tumors.

SECONDARY OBJECTIVES:

I. To record preliminary evidence of efficacy of PD-0332991 in children with recurrent CNS tumors.

II. To evaluate cyclin-dependent kinase (CDK)4/6, cyclin D1-3, Ink4a-ARF copy-number variations in available tumor tissue by array comparative, genomic hybridization (aCGH).

III. To explore the potential relationships between the pharmacokinetics of PD-0332991 and pharmacodynamic response (e.g. percentage change in absolute neutrophil count \[ANC\], platelet counts).

IV. To explore the pharmacogenetic polymorphisms in PD-0332991 metabolizing enzymes and transporters and relate these polymorphisms to PD-0332991 pharmacokinetics.

OUTLINE: This is a dose-escalation study.

Patients receive palbociclib isethionate orally (PO) once daily (QD) on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive palbociclib isethionate PO QD on days 1-21. Treatment repeats every 4 weeks for 26 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: palbociclib isethionate intervention 2: pharmacological study intervention 3: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol document:
ICF_001.pdf: 
NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
1 
 
SCREENING CONSENT 
 
Title of Study: Phase I study of CDK 4-6 inhibitor PD-0332991 (palbociclib; IBRANCE) in 
children with recurrent, progressive or refractory central nervous system tumors 
  
“You” refers to ‘you’ or ‘your child’ throughout this document. If you are the guardian of a 
minor or of a person under legal disability who is being asked to participate in this screening 
study, you may give consent on his/her behalf. 
 
INTRODUCTION: 
You have been asked to participate in a screening procedure for a research study.  In order to 
decide whether or not you should agree to take part in the screening study, you should know 
enough about its risks and benefits to make your decision. This process is known as informed 
consent. 
 
The study doctor or staff will explain the screening study to you and answer your questions about 
this testing.  Screening study only include people who choose to take part. Before making your 
decision, please read the information below carefully. Please ask questions about anything you 
do not understand. 
 
Once you understand the study, its risks and benefits, you will be asked to sign the form if you 
wish to take part. You will be given a copy to keep.  
 
Why is this study being done? 
The purpose of this study is to perform a test on a sample of your tumor which was removed at 
the time of your surgery and has been stored in a hospital laboratory. This screening procedure is 
a test to see if you might qualify to take part in a main research study using a study drug called 
PD-0332991 (IBRANCE). By signing this consent form, you are not agreeing to participate in 
the main research study, but only agreeing to have this test done.  
 
In order to participate in the main research study, your study doctor must assess whether your 
tumor tissue has a specific protein called Rb1 protein. This Rb1 protein is a protein that 
suppresses tumor growth. In certain tumors, cancer cells inactivate Rb1 protein so that it can no 
longer act as a tumor suppressor. However, over 60 percent of brain tumors in children still have 
Rb1 protein present and we want to find out whether your tumor has Rb1 protein or not. PD-
0332991 (IBRANCE) is a capsule that prevents the inactivation of Rb1, thereby suppressing 
tumor growth.    
 
You are being asked to participate in this study because you have a type of brain tumor other 
than diffuse pontine glioma (DIPG), medulloblastoma, or Atypical Teratoid Rhabdoid Tumor 
(ATRT) which has grown or come back after the usual treatment. Up to 55 people will be 
screened throughout the United States.  
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
2 
 
What is involved in this screening procedure? 
If you agree to have this screening test done, the study team will collect your date of birth to 
confirm your age, your tumor diagnosis, your height and weight and availability of your tumor 
tissue that was collected during a previous surgery.  
 
The screening procedure will also include sending a piece of tumor tissue that was collected 
during a surgery to a laboratory at University of California, San Francisco (UCSF).  Investigators 
from UCSF will look for the presence of Rb1 protein in the tumor tissue. If Rb1 protein is 
present, the study doctor or study nurse will discuss the main research study with you and you 
will be able to ask questions. If you are interested in taking part in the research study, you will be 
scheduled to have the rest of the eligibility procedures performed. You must meet all other 
eligibility criteria before you will able to participate in the main research study. 
 
How long will I be in the study? 
Since this is just a screening procedure, your involvement in this study will be minimal. The 
screening test will be done as soon as possible after you sign this consent.  The results will be 
given to your doctor who will discuss them with you and talk about the next steps. 
Can I stop being in the study? 
Yes, you can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop.     
What are the possible risks, side effects, and discomforts of this screening study? 
Since your tumor tissue has already been collected during the surgery, there are no risks involved 
with this screening test.   
 
What are the benefits of participating in this study? 
There are no benefits from having this tissue testing done other than to show if you might be able 
to participate in the main research study. 
 
What other choices do I have if I do not take part in this study? 
If you decide not to take part in this study, you will not be able to take part in the main research 
study.  You do have choices. For example: 
• you may choose to take part in a different study, if one is available 
 
Is my participation in this screening procedure voluntary? 
Yes. The choice to take part in this study or not is yours.   
 
Who will know about my participation in this screening study? 
Every effort will be made to keep your study record private. However, we cannot guarantee total 
privacy.  All records related to your involvement in this screening study will be stored in locked 
research files at:  (hospital name). Your identity in these records will be indicated by a unique 
number rather than by your name, and the information linking these case numbers with your 
identity will be kept separate from the screening records.  


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
3 
 
Your personal information may be given out if required by law.  If information from this study is 
published or presented at scientific meetings, your name and other personal information will not 
be used. Organizations that may look at and/or copy your medical records for screening, quality 
assurance, and data analysis include: 
 
• Your referring physician. 
• The local Institutional Review Board 
• The Pediatric Brain Tumor Consortium, which coordinates this study 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping screening safe for people 
• Representatives from pharmaceutical collaborators, such as the Pfizer company that 
supplies PD-0332991(IBRANCE) 
• University of California, San Francisco 
 
A description of this clinical trial may 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. 
 
What are the costs of taking part in this study? 
All costs associated with this screening procedure will be covered by the study budget. Neither 
you nor your insurance provider will be charged. 
 
Will I be paid if I take part in this screening procedure? 
Participation in this screening procedure is voluntary. No payment for participation will be 
given. 
 
What happens if I am injured because I took part in this study? 
There is no risk of injury involved because this screening test will use previously collected tumor 
sample material.  
 
What are my rights if I take part in this study? 
Taking part in the screening procedure is your choice.  You may choose either to take part or not 
to take part in the screening procedure.  No matter what decision you make, there will be no 
penalty to you and you will not lose any regular benefits.  Your medical care will not be affected 
if you do not participate in this screening procedure.  You can still get medical care from our 
institution.    
 
Who can answer my questions about the study? 
You can talk to the study doctor about any questions or concerns you have about this study. 
Contact the study doctor _(insert name of study doctor[s]) at _(insert telephone number). 
 
For questions about your rights while in this study, call the _(insert name of center) Institutional 
Review Board (a group of people who review the research to protect your rights) at _____(insert 
telephone number). 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
4 
 
Where can I get more information? 
You may call the National Cancer Institute's Cancer Information Service at:  
1-800-4-CANCER (1-800-422-6237) 
You may also visit the NCI Web site at http://cancer.gov/ 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/. For NCI’s general 
information about cancer, go to http://cancer.gov/cancerinfo/ 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 
Signature 
The above information has been explained to me and all of my current questions have been 
answered. 
 
I understand that I am encouraged to ask questions about any aspect of this screening study 
during the course of this study, and that such future questions will be answered by a qualified 
individual or by the investigator(s) listed on the first page of this consent document at the 
telephone number(s) given. I understand that I may always request that my questions, concerns 
or complaints be addressed by a listed investigator. 
 
By signing this form, I agree to participate in this screening study. A copy of this consent form 
will be given to me. 
 
PATIENT NAME:  _______________________________________________________ 
(Print Name) 
 
 
___________________________________________________________________________ 
Signature of Patient or Parent or Legal Guardian or Next of Kin 
 
Date 
 
 
 
__________________________________________________________________________  
Signature of 2nd Parent or Legal Guardian 
 
 
 
 
Date 
 
 
___________________________________________________________________________ 
Signature of Investigator or Designee 
 
 
 
 
Date 
 
 
___________________________________________________________________________ 
Signature of Witness  
 
 
 
 
 
 
Date 
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
  
Model Consent Form 
 
 
Study Title for Study Participants: 
Testing PD-0332991 (IBRANCE) to prevent the tumor growth in children 
with brain tumors 
 
Official Study title for Internet Search on http://www.ClinicalTrials.gov  
PBTC-042: Phase I study of CDK 4-6 inhibitor PD-0332991 (palbociclib; IBRANCE) in 
children with recurrent, progressive or refractory central nervous system tumors 
 
This form describes your participation in a clinical trial.  “You” refers to ‘you’ or ‘your child’ 
throughout this document. If the research subject is a minor child, you may give consent on 
his/her behalf. A clinical trial is a type of research study.  Clinical trials include only people who 
choose to take part.  This consent form gives you information about this study, to be discussed 
with members of your study team.   
 
Please take time to make the decision about whether to take part.  Please discuss this decision 
with your family and friends.  If there are any questions, ask your study doctor or health care 
team for more explanation.   
 
What is the usual approach to my type of cancer? 
You are being asked to take part in this research study because you have a brain tumor that has 
grown or come back or not responded to the usual treatment. People who are not in a study are 
usually treated with surgery, chemotherapy, radiation or other investigational agents.  
Sometimes, combinations of these are used and your study doctor can explain which may be best 
for you. These treatments can reduce symptoms and may stop the tumor from growing for 
several months or more. 
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. Please talk to your doctor 
about these other options. For example: 
• You may choose to have the usual approach described above 
• You may choose to take part in a different research study, if one is available 
• Or you may choose not to be treated for cancer but you may want to receive comfort care to 
relieve symptoms. 
 
Why is this study being done?  
Tumor cells grow and divide rapidly and uncontrollably. In normal cells, specific proteins called 
cyclin dependent kinases (CDK4 and 6) tightly control the process of cell division.  Another 
protein called Rb1 also regulates cell division and stops the cells from dividing. By stopping cell 
division, the Rb1 protein suppresses tumor formation in normal cells. But in cancer, CDK4 and 6 
are out of control and drive the cell to divide and form cancer. Tumor cells can sometimes 
inactivate Rb1 to help them divide continuously.   


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
In this study, we are testing a study drug called PD-0332991 (IBRANCE) that works by 
inhibiting the CDK4 and 6 proteins.  In animal studies, researchers have found that this drug 
works only if tumor cells have an intact Rb1 protein. Over 60 percent of brain tumors in children 
are likely to have an intact Rb1 protein. You have been approached for this study because your 
tumor has been identified to have an intact Rb1 protein. This drug is not FDA approved to treat 
brain tumors and is considered experimental.    
 
PD-0332991 (IBRANCE) has been previously tested in adults only. This study is the first time 
this drug is being given to children. Therefore we are testing different doses of the drug to 
determine the maximum dose that can be safely given to children with cancer.  Our hope is that 
PD-0332991 (IBRANCE) will be a more effective treatment for many types of childhood brain 
tumors. Approximately 42 - 50 people are expected to take part in this study throughout the 
United States. About 55 people will be screened in order to achieve this goal.  
   
The purposes of this study are:  
1. To find the highest dose of PD-0332991 (IBRANCE) that can be given without causing 
severe side effects in two study groups. 
2. To learn what side effects may occur when PD-0332991 (IBRANCE) is given. 
3. To learn how the body handles PD-0332991 (IBRANCE) by studying the levels of the 
drug in the blood. 
 
What are the study groups? 
Patients will be divided into two groups based on the type and intensity of prior treatment 
received. To find the highest and safest dose, all study participants in each group will get 
different doses of the study drug PD-0332991 (IBRANCE).  The first several study participants 
in each group will receive the lowest dose. If the initial dose level does not cause serious side 
effects, it will be given to other study participants at a higher dose. The doses will be increased 
for every group of study participants until side effects occur that require the dose to be lowered. 
If that dose level is safe, additional study participants will be included to receive PD-0332991 
(IBRANCE) at the same dose level.  
 
All study participants will get the study drug PD-0332991 (IBRANCE), in the form of oral 
capsules that should be taken with food. You will need to take PD-0332991 (IBRANCE) once a 
day for 21 days followed by 7 days break. This 4-week period is considered a course. You are 
encouraged to take your dose at the same time each day. It is important that you swallow the 
whole capsule (do not chew or crush). You should take plenty of water or take fluids to avoid 
dehydration if diarrhea occurs.  
 
You will be given a medication diary to record the number of capsules you take each day and the 
time they are taken. You will also be asked to return any unused capsules and the bottles of PD-
0332991 (IBRANCE) to your study doctor in each clinic appointment. If you vomit a dose of 
PD-0332991 (IBRANCE), you can re-dose if the capsule is seen intact in the vomited material. 
You will also be given a drug information handout and wallet card as a resource for yourself, 
caregivers and other health care providers. 
 
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
How long will I be in this study? 
You will receive PD-0332991 (IBRANCE) for 26 courses (about 2 years).  If you have benefited 
from receiving PD-0332991 (IBRANCE), and the study doctor agrees, you may be able to 
continue taking PD-0332991 (IBRANCE) for all 26 courses. Benefit means your disease is at 
least clinically and radiographically stable and you have not had any significant side effects. 
Your study doctor will continue to watch you for side effects and follow your condition for 30 
days after your last dose of PD-0332991 (IBRANCE).  
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of routine medical care for this 
type of cancer. However, there are some extra exams, tests and/or procedures that will need to be 
completed if you take part in this study. 
 
• Screening for Rb1 protein 
If you have any type of CNS tumors other than DIPG, medulloblastoma, or ATRT, you will be 
asked to participate in the screening portion of this study. A screening test for presence or 
absence of Rb1 will be performed at a laboratory at University of California (UCSF). Your study 
doctor will send glass slides containing tumor tissue that was collected from a previous surgery 
to the lab. The tumor tissue will be stained to identify the Rb1 protein. Based on this analysis, 
which will take about 14 days, we will learn whether or not you are eligible for the study.  
 
• 
Electrocardiogram (EKG) 
An electrocardiogram is a simple, painless test that records the heart’s electrical activity. To 
assess the activity of your heart, your study doctor will do an EKG before you start the treatment. 
An EKG will also be performed 3 hours after you take the study drug PD-0332991 (IBRANCE) 
on days 1, 8 and 15 of Course 1. An EKG will also be done at these time points: day 1 of 
Courses 2 and 3, every 12 weeks and again at the end of treatment.  
 
• Eye exam 
An eye exam will be performed by an ophthalmologist to make sure that you do not have or are 
not developing cataracts. It will be performed before you start the treatment and every 3 months 
while on study.  
 
• Pharmacokinetics (PK) blood (required) 
You are required to take part in this study because determining how the body handles this drug is 
an important part of the study. Your study doctor would like to learn how much PD-0332991 
(IBRANCE) stays in the blood for specific time points after the drug is taken. A total of about 2 
tablespoons (32 milliliters) of blood will be collected during the study.  
 
Blood samples will be collected from you to determine how much of the drug stays in the blood.  
Less than ½ teaspoon (about 2 mL) of blood will be collected each time from your arm or central 
line before you start treatment and  30 minutes, 1, 2, 4, 8, 10 (optional), 24 and 48 hours after 
your first dose of PD-0332991 (IBRANCE). You will be told NOT to take PD-0332991 
(IBRANCE) on Day 2 to collect the blood samples at 24 and 48 hour. Then, the same amount of 
blood will also be collected on Day 21 of Course 1 before you take PD-0332991 (IBRANCE) 
and 1, 2, 4, 8, 10 (optional) and 24 hours after you take PD-0332991 (IBRANCE).  


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
The risks are the same for any blood sample collected from your line.  If you don’t have a central 
line, the most common risks related to drawing blood from your arm are brief pain and possibly a 
bruise. 
 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Your samples are sent to the research doctor but no information identifying you (such as your 
name or medical record number) will be sent. Samples will be identified by a unique code only. 
Information that identifies you will not be given to anyone, unless required by law. If research 
results are published, your name and other personal information will not be used. 
 
You will not be billed for this required special study (Pharmacokinetics).  
 
• PK blood after stopping Dexamethasone (steroid treatment given to decrease swelling 
in your brain) (optional) 
This test is optional. The study doctor would like to find out how much PD-0332991 
(IBRANCE) stays in the blood after you stop taking dexamethasone. If you choose to take part 
and have received dexamethasone during the required PK studies, the study doctor will collect 
serial blood samples at least 2 weeks after stopping dexamethasone, and after 2 weeks of 
continuous treatment with PD-0332991 (IBRANCE). Less than ½ teaspoon (about 2 mL) of 
blood will be collected for each sample.  
 
• Pharmacogenetics (optional) 
If you choose to take part, a blood sample will be collected from you to determine if there are 
changes of certain genes that control how PD-0332991 (IBRANCE) is metabolized in the body. 
This test will require about 1 teaspoon (5 mL) of blood to be collected from your central line or a 
vein in your arm before you start the treatment. 
 
• Pre-trial tumor material for genomics (optional)  
Genomic research is research that studies the genes and their functions. Your blood and tumor 
cells contain genes, which are made up of DNA and which serve as the “instruction book” for 
cellular function. If you choose to take part, your study doctor would like to send a small piece of 
tumor material that is available from a previous surgery. The researchers will look for biological 
markers to help them understand the tumor better and how it might respond to the study drug. 
 
 
What will happen if I take part in this research study? 
A study plan below shows how often these tests and procedures will be done while you are on 
this research study.   
 
 
 
 
 
 
 
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
Study Plan 
 
Test /Procedure 
Pre- 
therapy 
Course 1 
Course 2 - Course 
26 
Completion/ 
Discontinuation 
 Of Treatment 
PHYSICAL ASSESSMENTS 
 
 
 
 
Medical history, physical exam, vital signs, 
performance status, neurological exam  
X 
  Every week  
Every month 
X 
Blood counts 
X 
  Every week 
Every week 
X 
Blood Chemistries 
X 
 Every week 
 Every month 
X 
Blood pregnancy test (for females who might 
be able to have children) 
X 
Before each course 
 
Spinal tap (if needed) 
X 
 
 
EKG  
X 
Day 1, 8, 15 
Day 1 of Course 2, 
3, 6, 9, 12, 15, 18, 
21 and 24  
X 
Eye exam 
X 
 
Course 3, 6, 9, 12, 
15, 18, 21 and 24 
 
Brain scan 
X 
 
Course 2, 4, 6 and 
then every 12 
weeks 
X 
Spine scan  (if needed) 
X 
 
Same as Brain MRI 
if needed 
X 
Take PD-0332991 (IBRANCE) once a day; 
record in the pill diary 
 
X 
X 
 
Optional research tests 
 
Screening Pre-trial tumor materials for Rb1 
testing  (required for patients with all types of 
CNS tumors except DIPG, medulloblastoma, 
ATRT) 
X 
 
 
 
Pharmacogenetics (if consented) 
X 
 
 
 
Pharmacokinetics blood (required) 
X 
Day 1, 2, 3, 
21 and 22 
 
 
PK blood after discontinuation of 
dexamethasone (if consented) 
 
Any time after stopping  
dexamethasone 
 
Pre-trial tumor materials for Genomics (if 
consented) 
X 
 
 
 
Tumor Tissue and blood for Biorepository (if 
consented) 
X 
 
 
 
 
 
 
 
 
 
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
What possible risks can I expect from taking part in this study?  
 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work, school or home and spend more time in the hospital or 
doctor’s office than usual 
• You may be asked sensitive or private questions which you do not normally discuss 
 
The PD-0332991 (IBRANCE) used in this study may affect how different parts of your body 
work such as your liver, kidneys, heart, and blood. Your study doctor will be testing your blood 
and will address any changes that may affect your health.  
 
There is also a risk that you could have side effects from PD-0332991 (IBRANCE).   
 
Here are important points about side effects: 
• Your study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how to make side effects less of a problem: 
• Tell your study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• Your study doctor may be able to treat some side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
Let your study doctor know of any questions you have about possible side effects. You can ask 
your study doctor questions about side effects at any time. The tables below show the most 
common and the most serious side effects that researchers know about. There might be other side 
effects that researchers do not yet know about. If important new side effects are found, your 
study doctor will discuss these with you. 
 
Side effects of PD-0332991 (palbociclib; IBRANCE) 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving palbociclib (PD-0332991), more than 20 and up to 100 may have: 
• 
Anemia which may require blood transfusion 
• 
Nausea 
• 
Tiredness 
• 
Infection, especially when white blood cell count is low 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving palbociclib (PD-0332991), from 4 to 20 may have: 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
• 
Blurred vision, watering eyes 
• 
Dry eye, skin 
• 
Constipation, diarrhea, vomiting 
• 
Sores in the mouth which may cause difficulty swallowing 
• 
Fever 
• 
Bruising, bleeding 
• 
Loss of appetite 
• 
Changes in taste 
• 
Headache 
• 
Nose bleed 
• 
Hair loss, rash 
 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this 
study. The effects of PD-0332991 (IBRANCE) used in this study could be very damaging to an 
unborn baby.  
Women of childbearing potential must have a negative pregnancy test prior to study entry. 
Women of childbearing potential must agree to use an effective method of birth control during 
the study and for 97 days after completion of treatment. Check with your study doctor about 
what types of birth control, or pregnancy prevention, to use while in this study.  
 
In animal studies, male reproductive organ effects were seen when PD-0332991 (IBRANCE) 
was given to rats and dogs for at least 3 weeks. The effects include decay of seminiferous tubule 
structure (tubes in the testes where sperm is produced) and a decrease in semen fluid secretion 
(ability of semen to flow). These effects were reported minimal to severe depending on the dose 
given. These toxicities were seen at drug levels that are used in clinical research studies.  
However, reversal of these effects were seen either partially or completely, at least 4 weeks after 
PD-0332991(IBRANCE) is stopped. It is currently unknown what these findings mean for 
patients treated with palbociclib over time. If you are a male patient and want to have children at 
a later time, we recommend that you preserve your sperm prior to the study entry. Male patients 
must agree to use effective contraception during the study and for 97 days after completion of 
treatment. 
 
Routine studies in rats revealed that some of the animals developed cataracts (clouding of the eye 
lens) after being given PD-0332991 (IBRANCE) for 6 months.  It is currently unknown what 
these findings mean for patients treated with PD-0332991 (IBRANCE) over time. You will have 
an eye examination done by your eye doctor to make sure that you do not have or are not 
developing cataracts before being registered on this study and every 3 months while on 
treatment.  
 
What possible benefits can I expect from taking part in this study? 
Taking part in this study may or may not make your health better. This study may help doctors 
learn more about how PD-0332991 (IBRANCE) affects your cancer. This information could help 
future cancer patients.  
 
 
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
Can I stop taking part in this study? 
Yes.  You can decide to stop at any time.  If you decide to stop for any reason, it is important to 
let your study doctor know as soon as possible so you can stop safely. If you stop, you can 
decide whether or not to let your study doctor continue to provide medical information to the 
organization running the study.   
 
Your study doctor will provide any new information or changes in the study that may affect your 
health or willingness to continue in the study. 
 
The doctor may decide to take you out of the study: 
• If the side effects are too harmful to you 
• If you need a treatment not allowed on this study 
• If your tumor returns or grows 
• If you do not follow the study rules 
• If new information becomes available 
• If the study is stopped by the sponsor, IRB or FDA 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  No matter what your decision is, and even if your 
decision changes, there will be no penalty.  You will not lose medical care or any legal rights.   
 
For questions about you rights while taking part in this study, call the (institution name) 
Institutional Review Board (a group of people who review the research to protect your rights) at 
(institution telephone number). 
 
What are the costs of taking part in this study? 
PD-0332991 (IBRANCE) will be supplied at no charge while taking part in this study. It is 
possible that PD-0332991 (IBRANCE) may not continue to be supplied while you are on the 
study. Although not likely, if this occurs, your study doctor will talk to you about other options. 
 
You or your health plan/insurance company will need to pay for all of the other costs of treating 
your cancer while in this study, including the cost of tests, procedures, or medicines to manage 
any side effects, unless your study doctor tells you certain tests are supplied at no charge. Before 
making a decision about participating in this study, you should check with your health plan or 
insurance company to find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 
What happens if I am injured because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The study sponsor will not offer to pay for medical treatment for 
injury. Your insurance company may not be willing to pay for study-related injury.  If you have 
no insurance, you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it.  
Your personal information may be given out if required by law.  However, the researchers will 
do their best to make sure that any information that is released will not identify you. Some of 
your health information, and/or information about your specimen, from this study will be kept in 
a central database for research. 
 
There are organizations that may look at and/or receive copies of your medical records for 
research, quality assurance, and data analysis. Some of these organizations are: 
• The study sponsor and the representatives from the pharmaceutical collaborator (Pfizer) who 
manufactures PD-0332991 (IBRANCE)  
• The local Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting people who take part in the study.  
• The Pediatric Brain Tumor Consortium, who coordinates this study 
• Federal agencies such as the Food and Drug Administration (FDA), the Office of Human 
Research Protections (OHRP) and the National Cancer Institute (NCI) in the U.S., and 
similar ones if other countries are involved in the study.  
 
Coded patient data and images from brain scans will be transmitted over the Internet to be 
analyzed by other PBTC researchers.  The PBTC has procedures (data encryption) in place to 
make electronic transmission of research information as secure as possible.  The data security 
involves coding the data in a way that only the authorized receiver can decode the data.  The 
method used to transfer information is more secure than many methods used by financial 
institutions when conducting business over the Internet.   
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Website will not include information that can identify you.  At most the 
Website will include a summary of the results.  You can search this Website at anytime 
 
Who can answer my questions about this study?  
You can talk to your study doctor about any questions or concerns related to this study.  Contact 
your study doctor (Physician’s name) at (Physician’s telephone number). 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.  
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
 
Additional Studies Section: 
 
This part of the consent form is about optional studies that you can choose to participate. You 
will not get health benefits from any of these studies. The researchers leading these optional 
studies hope the results will help other people with cancer in the future. 
 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say “no” to any or all of these optional studies. If you sign up for but cannot complete any of 
the studies for any reason, you can still take part in the main study.  
 
What are the possible risks?  
1. The most common risks related to drawing blood from your arm are brief pain and 
possibly a bruise.  
2. There is a risk that someone could get access to the personal information in your medical 
records or other information researchers have stored. 
3. There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique. The 
researchers believe the chance that someone will identify you is very small, but the risk 
may change in the future as people come up with new ways of tracing information. 
4. There can also be a risk in knowing genetic information. New health information about 
inherited traits that might affect you or blood relatives could be found during a study. The 
researchers believe the chance these things will happen is very small, but cannot promise 
that they will not occur. In general, we will not give you any individual results from the 
study of the samples you gave us.  This is because it will probably be a long time before 
we will know how to interpret the information accurately.   In the rare instance that one 
of the genes tested might turn out to be an important risk factor for a disease, and having 
that information could allow you to take steps to prevent, detect earlier, or better treat that 
disease, we will ask you whether you want to know those results. If so, we will contact 
you and your doctor to discuss more testing.  
5. Some of your genetic and health information may be placed in central databases that may 
be public, along with information from many other people. The data resulting from the 
genetic research may be deposited into a public or controlled access database made 
available to other researchers. Information that could directly identify you will not be 
included. However, people may develop ways in the future that would allow someone to 
link your genetic or medical information in our databases back to you. For example, 
someone could compare information in our databases with information from you (or a 
blood relative) in another database and be able to identify you (or your blood relative). It 
also is possible that there could be violations to the security of the computer systems used 
to store the codes linking your genetic and medical information to you. 
 
How will information be kept private? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1. When your sample(s) is sent to the researchers, no information identifying you (such as 
your name) will be sent. Samples will be identified by a unique code only. 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
2. The list that links the unique code to your name will be kept separate from your sample 
and health information.  
3. Information that identifies you will not be given to anyone, unless required by law. 
4. If research results are published, your name and other personal information will not be 
used. 
 
 
What are the possible benefits? 
You will not benefit from taking part. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
What if I change my mind? 
If you decide you no longer want research samples to be used, you can contact your study doctor 
in writing, (insert name of study doctor) who will let the researchers know. Then, any sample 
that remains in the bank will no longer be used and related health information will no longer be 
collected. Samples or related information that have already been given to or used by researchers 
will not be returned. If data has been submitted to a data repository, please include in your letter 
a request to retrieve your data.   
 
What if I have more questions? 
If you have questions about the use of your samples for research, contact the study doctor,  
[Physician’s name] at [Physician’s telephone number]. 
 
For each of the optional studies below, please circle your response and then initial and date on 
the line provided.   
 
1. Optional Sample Collection for research studies and storage:  
Researchers are trying to learn more about cancer. Much of this research is done using samples 
from your tissue, blood, urine, or other fluids. Through these studies, researchers hope to find 
new ways to prevent, detect, treat, or cure health problems. Some of these studies may be about 
genes. Genes carry information about features that are found in you and in people who are 
related to you. Researchers are interested in the way that genes affect how your body responds to 
treatment. If you do not have tissues collected during or after treatment, ask your doctor how you 
can donate tissue in the future. 
 
i. 
Optional Sample Collection for Repository: 
If you choose to take part in the sample collection for the repository, tumor tissue from a 
previous surgery is needed and a blood sample is strongly encouraged to provide stored genetic 
material from your tumor and your healthy tissue. The researchers ask your permission to store 
and use your samples and related health information (for example, your response to cancer 
treatment, results of study tests and medicines you are given) for future medical research.  The 
future research that may be done is unknown at this time but may include genomic studies. These 
samples will be stored at the PBTC Central Review and Biorepository (PBTC CRB) where 
similar samples from other subjects are stored until requested for analysis.  
 
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
 
I choose to have my tumor tissue specimen collected and I agree that this tumor tissue and 
related information may be used for the test described above.  
 
 
YES 
_______________ 
NO 
______________ 
 
 
I choose to have my blood specimen collected and I agree that this blood sample and related 
information may be used for the test described above.  
 
 
YES 
_______________ 
NO 
______________ 
 
 
ii. 
Leftover sample storage for future research: 
If you choose to take part, tumor material collected as a part of this study but not completely 
used for the analysis will be stored in the repository for future unspecified research. The 
researchers ask your permission to store and use your samples and related health information (for 
example, your response to cancer treatment, results of study tests and medicines you are given) 
for medical research. The research that may be done is unknown at this time.  
 
I agree to have my specimen collected and I agree that my specimen sample(s) and related 
information may be used for the laboratory study (ies) described above. 
 
 
 
YES 
_______________ 
NO 
______________ 
 
2. Optional Laboratory studies  
 
i. 
Pharmacogenetic Study:  
If you choose to take part in this study, a blood sample will be collected from you for research to 
determine if changes in certain genes are related to how PD-0332991 (IBRANCE) moves 
through your body.  The results of this test will only be used for research and not to guide your 
medical care. This test will require about 1 teaspoon (5 mL) of blood to be collected from your 
central line or arm before you start the treatment. The risks are the same for any blood sample 
collected from your line.  If you don’t have a central line, the most common risks related to 
drawing blood from your arm are brief pain and possibly a bruise. 
 
I choose to have my specimen collected and I agree that this blood sample and related 
information may be used for the test described above.  
 
 
YES 
_______________ 
NO 
______________ 
 
 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
ii. 
PK blood after stopping Dexamethasone: 
If you choose to take part and have received dexamethasone during the required PK studies, the 
study doctor will collect serial blood samples at least 2 weeks after stopping dexamethasone, and 
after 2 weeks of continuous treatment with PD-0332991 (IBRANCE). These samples will be 
collected at a routine clinic visit before you start treatment, and at 1, 2, 4, 8, 10 (optional) and at 
24 hours after the dose. Less than ½ teaspoon (about 2 mL) of blood will be collected at each 
time point from your arm or central line. The risks are the same for any blood sample collected 
from your line.  If you don’t have a central line, the most common risks related to drawing blood 
from your arm are brief pain and possibly a bruise. 
 
I choose to have my specimen collected and I agree that my blood sample(s) and related 
information may be used for the laboratory study described above. 
 
 
 
YES 
_______________ 
NO 
______________ 
 
 
iii. 
Pre-trial tumor material for genomics  
 
Your blood and tissue samples contain genes, which are made up of DNA and serve as the 
“instruction book” for the cells that make up our bodies.  If you choose to take part, your study 
doctor would like to send a small piece of tumor material that is available from a previous 
surgery.  The researchers will look for biological markers to help them understand the tumors 
better. The tumor material will not put you at risk as it will be taken from tumor already store 
from a previous surgery.   
 
I agree that my tumor material and related information may be used for the laboratory study 
described above. 
 
YES 
_______________ 
NO 
______________ 
 
 
iv. 
Contact regarding incidental genetic findings 
If you chose to participate in genetic testing of tumor samples as described in section 2 (iii), you 
may choose to be contacted in the future if we find incidental genetic abnormalities in your 
samples. The results of these studies or your choice will not affect your participation in the 
current study. 
 
I would like to be contacted in the future if significant incidental genetic abnormalities are found 
in my samples. 
 
 
YES   
 
 
             NO        
 
 
 
 
 
This is the end of the section about optional studies. 


NCI Protocol #: PBTC-042 
Version Date: 28 June 2018 
 
 
 
 
 
 
 
SIGNATURE 
 
I have been given a copy of all _____ pages of this form.  I have read it or it has been read to me.  
I understand the information and have had my questions answered.  I agree to take part in the 
main study and any additional studies where I circled ‘yes’. 
 
 
PATIENT NAME:  _______________________________________________________ 
 
 
 
 
 
(Print Name) 
 
__________________________________________________ 
   __________________ 
Signature of Patient or Parent or Legal Guardian or Next of Kin 
 
Date 
 
 
___________________________________________________ 
   __________________ 
Signature of 2nd Parent or Legal Guardian  
 
 
 
Date 
 
 
___________________________________________________ 
   __________________ 
Signature of Investigator or Designee 
 
 
 
 
Date 
 
 
___________________________________________________  
   __________________ 
Signature of Witness  
 
 
 
 
 
 
Date 
 
 

Prot_SAP_002.pdf: 
NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
NCI Protocol #: 
PBTC-042 
 
Local Protocol #: 
PBTC-042 
 
TITLE:  Phase I study of CDK 4-6 inhibitor PD-0332991 (palbociclib; IBRANCE) in children 
with recurrent, progressive or refractory central nervous system tumors 
 
Coordinating Center: 
Operations, Biostatistics and Data Management Core (OBDMC) for the 
Pediatric Brain Tumor Consortium (PBTC), St. Jude Children’s Research 
Hospital 
 
 Principal Investigator: 
David Van Mater, MD, PhD 
 
 
 
 
 
 
 
  
 
 
 
Co- Chair:                                
Sridharan Gururangan, FRCP (Eden) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co- Chair: 
Sarah Leary, M.D. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
PBTC Biostatistician 
Arzu Onar-Thomas, PhD 
 
 
 
 
 
 
 
PBTC Biostatistician 
Jie Huang, MS 
 
 
 
 
 
 
 
 
 
 
 
PBTC Protocol Coordinator 
Emily Carps, MBA, CCRA  
  
 
 
 
 
 
 
 
 
PBTC Neuroimaging Center 
Tina Young Poussaint, M.D. 
 
 
 
 
 
 
 
  
 
 
Biological Correlates Laboratory 
Donald W.(Will) Parsons, M.D, 
PhD 
  
 
  
 
 
 
 
 
 
 
Biological Correlates Laboratory 
Joanna J. Phillips, MD, PhD 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRA Committee Rep 
Charlene Flahiff, MS, CCRP 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Nursing Committee Rep 
Megan Urban, MSN, CPNP 
 
 
 
 
 
Pharmacokinetics Laboratory 
Clinton Stewart, PharmD 
 
 
 
 
 
 
 
This protocol is for research purposes only, and should not be copied, redistributed or used for any other purpose.  The 
procedures in this protocol are intended only for use by clinical oncologists in carefully structured settings, and may not 
prove to be more effective than standard treatment.  A responsible investigator associated with this clinical trial should be 
consulted before using or attempting any procedure in this protocol. Contents of this document may not be extracted 
without permission from the Study Chair. 
 
NCI Supplied Agent(s): NA 
Other Agent Name(s), NSC# and Supplier: PD-0332991 (palbociclib; IBRANCE)/Pfizer, NSC# 
772256  
IND Sponsor: David Van Mater, MD, PhD, 
/IND# 122656 
Protocol Type/ Version#/ Version Date: Amendment/ Version #10.0/ Version Date: 28 June 2018 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
Pediatric Brain Tumor Consortium Institutions and Principal Investigators 
Arzu Onar-Thomas, Ph.D.* 
 
 
 
 
 
 
 
 
Giles Robinson, MD 
 
 
 
 
 
 
 
Patricia Baxter, M.D. 
 
 
 
 
 
 
 
 
Daniel Landi, MD 
 
 
 
 
 
 
 
 
 
Ian Pollack, M.D. 
 
 
 
 
 
 
 
Kathy Warren, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eugene Hwang, M.D. 
 
 
 
 
 
 
 
Stewart Goldman, M.D. 
 
 
 
 
 
 
 
 
Michelle Monje, MD, PhD 
 
 
 
 
 
 
 
 
 
 
 
Maryam Fouladi, M.D. 
 
 
 
 
 
  
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Ira Dunkel, M.D. 
 
 
 
 
 
 
Girish Dhall, MD 
 
  
 
 
 
 
 
 
*Does not have patient care responsibilities 
 
Temporary Participating Member for PBTC-042 
 
 
Sarah Leary, M.D. 
  
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
SCHEMA 
 
Description 
This is a multicenter, Phase I trial for children with Retinoblastoma Protein 1 (Rb1) positive 
recurrent, progressive or refractory central nervous system tumors.  
In the recent years there have been several clinical trials in adults with cancer utilizing small 
molecule inhibitors targeting cell cycle regulatory genes such as CDKs (cyclin-dependent kinase). 
In normal cells, these kinases are kept under control by a gene, however, this gene is frequently 
deleted in cancers and these two kinases are uncontrollably activated which drives the cell to divide 
and form cancer. This trial is using PD-0332991 (palbociclib; IBRANCE), a selective CDK 
inhibitor, to be evaluated in children with CNS tumors.  
 
PD-0332991 (Pfizer Corporation, USA) is an orally active, water soluble, cell-permeable highly 
specific inhibitor of CDK4 and 6. It is designed to shut down the activity of molecules, CDK4 and 6 
that drive cell division. PD-0332991 is expected to work only if the cancer cells demonstrate 
expression of the tumor suppressor retinoblastoma (Rb1) protein which is needed to control cell 
growth even if CDK4/6 is inhibited. A screening test for presence or absence of Rb1 will therefore 
be performed in all types of CNS tumors except diffuse pontine glioma (DIPG), medulloblastoma, 
or Atypical Teratoid Rhabdoid Tumor (ATRT) to confirm eligibility for this trial. .   
 
Schema 
This is a dose escalation trial of PD-0332991 to determine the maximum tolerated dose in children 
with recurrent brain tumors. PD-0332991 is taken orally once a day for 21 days followed by a week 
rest. One course is therefore equivalent to 28 days. Therapy may continue for up to two years (26 
courses) in the absence of disease progression or unacceptable toxicity.   
 
Dosing is based on BSA calculated at the beginning of each course. The starting dose is 50 mg/m2 
for stratum I and stratum II. PD-0332991 dose escalations will be performed according to the table 
below until the maximum tolerated or recommended Phase II dose is reached. Since 
myelosuppression is the main dose limiting toxicity (DLT) of this drug, patients who have been 
more heavily pretreated are likely to experience hematologic toxicity with this agent. Therefore, 
patients will be divided into two strata; stratum I- patients who have received either focal 
radiotherapy (RT) only or focal RT ± ≤ 4 prior myelosuppressive chemotherapy and/ or biologic 
therapy regimens or stratum II- those who have received > 4 prior regimens (either chemotherapy 
or biologic agent), ± craniospinal irradiation, and ± myeloablative chemotherapy plus bone marrow 
or peripheral blood stem cell rescue. 
 
Enrollment to Stratum I is now complete and accrued 21 patients at dose level 1 (n=3), 2 (n=12), 
and 3 (n=6). Two patients enrolled at dose level 3 were inevaluable for DLT. Of the 10 evaluable 
patients, 2 of 4 patients at dose level 3 experienced a DLT of grade 4 neutropenia. Hence the MTD 
was exceeded at dose level 3. The maximum tolerated dose (MTD) for stratum I was dose level 2 
(75 mg/m2/day for 21 days). Since the possibility of myelosuppression is expected to be greater in 
patients enrolled in stratum II (heavily pretreated patients), we consider it more prudent to 
commence enrollment of patients at dose level 1 which is 50 mg/m2/day. An MTD is currently 
being determined for this stratum. 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Stratum I and II - PD-0332991 (IBRANCE) Dosing Regimen and BSA 
Restrictions 
 
Dose Level 
Dose (mg/m2) 
BSA (m2) 
 1* 
50 
≥ 1.20 
  2** 
75 
≥ 0.93 
3 
95 
≥ 0.70 
*Starting dose for stratum II 
** MTD for stratum I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
TABLE OF CONTENTS 
 
SCHEMA ............................................................................................................................................ 5 
TABLE OF CONTENTS .................................................................................................................. 7 
1. 
OBJECTIVES ............................................................................................................................. 9 
1.1 
Primary Objectives ................................................................................................................ 9 
1.2 
Secondary Objectives ............................................................................................................ 9 
2 
BACKGROUND ........................................................................................................................ 10 
2.1 
Study Disease ...................................................................................................................... 10 
2.2 
PD-0332991 ........................................................................................................................ 12 
2.3 
Rationale.............................................................................................................................. 26 
2.4 
Correlative Studies Background.......................................................................................... 27 
3 
PATIENT SELECTION ............................................................................................................. 30 
3.1 
Screening Criteria ................................................................................................................ 30 
3.2 
Eligibility for Treatment Criteria ........................................................................................ 31 
3.3 
Exclusion Criteria ................................................................................................................ 34 
3.4 
Treatment at Primary Institution ......................................................................................... 35 
3.5 
Criteria to Start Treatment................................................................................................... 35 
4 
REGISTRATION and ENROLLMENT PROCEDURES ......................................................... 36 
4.1 
CTEP Investigator Registration Procedures ........................................................................ 36 
4.2 
CTSU Registration Procedures ........................................................................................... 37 
4.3 
Enrollment Procedures ........................................................................................................ 38 
5 
TREATMENT PLAN................................................................................................................. 40 
5.1 
Agent Administration .......................................................................................................... 40 
5.2 
Dose Limiting Toxicity ....................................................................................................... 42 
5.3 
Criteria for starting subsequent courses .............................................................................. 43 
5.4 
Concomitant Medications and Supportive Care Guidelines ............................................... 43 
5.5 
Duration of Therapy ............................................................................................................ 45 
6 
DOSING DELAYS/ DOSE MODIFICATION ......................................................................... 47 
6.1 
Notification of Study Chair ................................................................................................. 47 
6.2 
Hematologic and Non-Hematologic Adverse Events and Management ............................. 47 
7 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ...................................... 48 
7.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR) ................................... 49 
7.2 
Adverse Event Characteristics ............................................................................................ 51 
7.3 
Expedited Adverse Event Reporting ................................................................................... 51 
7.4 
Routine Adverse Event Reporting....................................................................................... 54 
7.5 
Secondary Malignancy ........................................................................................................ 54 
7.6 
Second Malignancy ............................................................................................................. 55 
8 
AGENT INFORMATION .......................................................................................................... 56 
8.1 
PD-0332991 (palbociclib; IBRANCE®) ............................................................................ 56 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................................................. 59 
9.1 
Integral Biomarker Studies.................................................................................................. 59 
9.2 
Laboratory Correlative Studies ........................................................................................... 60 
9.3 
Pathology and Exploratory Correlative Studies .................................................................. 64 
9.4 
Neuroimaging Studies ......................................................................................................... 68 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
10 
STUDY CALENDAR ............................................................................................................ 69 
11 
MEASUREMENT OF EFFECT............................................................................................. 71 
11.1 
Tumor Response Criteria ................................................................................................. 71 
12 
DATA REPORTING/ REGULATORY REQUIREMENTS ................................................. 72 
12.1 
Data Reporting ................................................................................................................. 72 
12.2 
Collaborative Agreements Language .............................................................................. 72 
12.3 
Participant and Data Confidentiality ............................................................................... 73 
13 
STATISTICAL CONSIDERATIONS.................................................................................... 75 
13.1 
Evaluability ...................................................................................................................... 75 
13.2 
Study Design/Endpoints .................................................................................................. 75 
13.3 
Sample Size/Accrual Rate ............................................................................................... 77 
13.4 
Analysis of the Adverse Event Data: ............................................................................... 78 
13.5 
Data analysis plan for the secondary objectives: ............................................................. 78 
13.6 
Statistical Analysis of Pharmacokinetics ......................................................................... 79 
14 
REFERENCES ....................................................................................................................... 80 
Appendix A 
 Performance Scales ............................................................................................... 83 
Appendix B 
 Medications that may cause QTc Prolongation .................................................. 84 
Appendix C 
 Potential Drug Interactions with PD-0332991 (palbociclib; ............................. 86 
IBRANCE) ........................................................................................................................................ 86 
Appendix D 
 Dosing Tables for PD-0332991 (palbociclib; IBRANCE) .................................. 87 
Appendix E 
 Patient’s Diary ....................................................................................................... 88 
Appendix F  
Patient Drug Information Handout and Wallet Card ........................................ 90 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
1. OBJECTIVES 
1.1 
Primary Objectives  
1.1.1 To determine the maximum tolerated dose (MTD)/Phase II recommended dose and 
describe toxicities related to PD-0332991 in children with Retinoblastoma Protein 1 (Rb1) 
positive recurrent, progressive, or refractory primary CNS tumors. MTD will be 
determined separately in less-heavily pre-treated vs. heavily pre-treated patients. 
1.1.2 To determine plasma pharmacokinetics of PD-0332991 in children with Rb1positive 
recurrent, progressive or refractory primary CNS tumors 
 
1.2 
Secondary Objectives 
1.2.1 To record preliminary evidence of efficacy of PD-0332991 in children with recurrent 
CNS tumors 
1.2.2 To evaluate CDK4/6, cyclin D1-3, Ink4a-ARF copy-number variations in available tumor 
tissue by array comparative, genomic hybridization (aCGH) 
1.2.3 To explore the potential relationships between the pharmacokinetics of PD-0332991 and 
pharmacodynamic response (e.g. percentage change in absolute neutrophil count (ANC), 
platelet counts) 
1.2.4 To explore the pharmacogenetic polymorphisms in PD-0332991 metabolizing enzymes 
and transporters and relate these polymorphisms to PD-0332991 pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
2 
BACKGROUND 
2.1 
Study Disease 
Recurrent pediatric primary Central Nervous System (CNS) tumors 
The incidence of pediatric central nervous system (CNS) tumors is approximately 4000 new 
cases per year in the United States. While excellent cure rates can be achieved with low-grade 
gliomas and medulloblastoma with either surgery alone or in combination with chemotherapy 
and radiotherapy, the outcome for other types of CNS tumors remains suboptimal. Furthermore, 
cure rate in children with recurrent CNS tumors following standard therapy is dismal. Recent 
studies at the genomic level have revealed specific molecular alterations that drive the relentless 
progression of these tumors and might serve as targets for specific inhibitors that can control 
tumor proliferation and spread and, in contrast to cytotoxic therapy, with less damage to normal 
tissues.5,6  
Cell cycle phases in mammalian cells (accelerators, brakes, and check points) 
Tumor cell proliferation requires repetitive cell divisions involving doubling of DNA content 
(during the synthetic or S phase) and halving of the genome during mitosis (M phase) that results 
in two identical cells. Between the S and M phase, a gap occurs referred to as G1 during which 
the cell decides to commit to another round of cell division or exit the cell cycle and enter a state 
of quiescence called the G0 phase.7 During the G1 phase, cells grow and prepare for 
chromosomal replication during the S phase. Following the S phase, the cell enters into another 
gap phase called G2 during which time the cell prepares for the equal division of its DNA into 
two identical daughter cells (M phase). Checkpoints are transitions between various phases of the 
cell cycle when the integrity of replication and division are carefully monitored before allowing 
the cell to move to the next phase.7 Any error in the process of replication will result in the 
normal cell arresting the cell cycle till the error can be rectified. Cancer cells however continue 
the replication process despite the breach in DNA integrity. The different phases of the cell cycle 
are orchestrated by two distinct groups of proteins, the cyclins and their closely associated 
cyclin-dependent kinases (CDK).7 In mammalian cells, cyclins and the CDKs can be divided into 
G1 Cyclins (cyclin D1-3, and E) and CDK 4, 6, and 2; S phase cyclins (cyclins A and E) and 
CDK2, and mitotic cyclins (Cyclin A and E) and CDK 1 and 2.7 The “brakes” in the cell cycle 
are by regulation of CDK activity that can occur at multiple levels including phosphorylation and 
dephosphorylation of CDK, cyclin synthesis and degradation, and expression/degradation/ 
availability of naturally occurring protein inhibitors and subcellular localization of these 
regulatory components. The two main classes of inhibitors include inhibitor of CDK4 (INK4) 
family of inhibitors and the CDK inhibitor protein (CIP)/kinase inhibitor protein family of 
inhibitors.7 Whereas the INK4 family of inhibitors (p16INK4A and p14ARF, p15INK4B, p18INK4C, and 
p19INK4D) specifically inhibits only CDK4/6 during G1, CIP/KIP (p21CIP1, p27KIP1, p57KIP2) are 
capable of inhibiting kinases and cyclins during all phases of the cell cycle.7 
G1-S transition in the mammalian cell cycle is divided into the early G1(pre-restriction point (RP) 
during which activation CDK-4 /Cyclin D complex occurs following release of INK4 from 
CDK4/6.7 This results in hypophosphorylation of the retinoblastoma protein (Rb) and partial 
release of the E2F-DP1 transcription complex. In late G1, release of cyclin E/CDK2 from the 
inhibitory effect of p27KIP1, results in hyperphosphorylation of Rb1 and complete release of E2F-
DPI complex which then binds to promoter regions of genes whose transcription are necessary 
for S phase entry and progression (Figure 1).7,8  


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
 
Figure 1: The CDK4,6/p16/Rb-E2F pathway 
 
Alterations of cell cycle regulating genes in pediatric CNS tumors 
Recent studies on the genomic aberrations of pediatric CNS tumors have demonstrated that a 
subset harbor focal gains in CDK4, CDK6, Cyclin D1-3, or homozygous Ink4a-ARF loss 
suggesting that patients with these tumors may benefit from therapies targeting CDK4/6. About 
35% of pediatric brainstem gliomas harbor focal gains in CDK4, CDK6, or cyclin D1-3.9  
About 20% of pediatric brainstem gliomas have been shown to have p16 loss.10 Although one 
report did not identify any Rb1 mutations in 11 DIPG (Diffuse Intrinsic Pontine Glioma) tumor 
samples,11 in another recent unpublished study homozygous Rb1 deletions have been observed in 
approximately 30% of tumor specimens (Oren Becher MD., Durham, NC 2013; unpublished 
observations). In a yet unpublished study of over 50 DIPG samples from St. Jude children’s 
Research Hospital no Rb1 mutations were found (Suzanne Baker Ph.D, Memphis, TN; personal 
communication 2013). On this basis, patients with DIPG will not be screened for Rb1 
mutation prior to enrollment. 
Homozygous Ink4a-ARF loss is seen at the genomic level in 20% of non-brain stem gliomas.12  
In addition focal gain in CDK6, CDK4, and Cyclin D2 is observed in up to 6% in these 
tumors.12,13 Rb1 deletions have been observed with this tumor subtype in only 5/49 (10%) of 
cases.13 In pilocytic astrocytomas (PA), the most common subtype of pediatric CNS tumors, a 
subset of patients with poor prognosis harbor p16 loss (13.6% or 9/66), suggesting that some 
recurrent PAs may respond to CDK4/6 inhibitor.14 
Homozygous CDKN2A (the gene for p16) deletions have been observed to be a poor prognosis 
marker in ependymoma.15 Rb1 and p16 deletions were seen in 22 of 92 (24%) and 22 of 89 
(25%) of ependymomas respectively.16 Therefore recurrent ependymoma patients may benefit 
from a CDK 4/6 inhibitor but should be screened for the presence of Rb1 protein expression by 
immunohistochemistry (IHC) prior to enrollment on this trial.  
CDK6 is overexpressed in 30% of medulloblastomas. Overexpression of CDK6 correlates 
significantly with poor prognosis and represents an independent prognostic marker of overall 
survival on multivariate analysis (P = 0.02).17 In contrast, Rb1 homozygous loss or Rb1 
mutations have  only been rarely observed in this tumor.17-19 In a genomic analysis of 22 
medulloblastoma samples, Parsons et al., found no Rb1 mutations.18  Jones et al., in another 


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study observed only one non-synomyous single nucleotide variation (SNV) in 1/38 
medulloblastoma tumors.19 Similarly, atypical teratoid rhabdoid tumors (ATRT) have not been 
found to harbor Rb1 mutations.20 Kieran et al., evalauted 25 Rhabdoid (n = 8) ATRT (n = 17) 
newly diagnosed and histologically verified tumor samples using an Oncomap-3 platform to 
interrogate 983 genes for mutations and amplifications. Other than SMARCB1 mutations in all 
samples and NRAS mutation in one case of a brain ATRT, no other gene alterations were 
observed including Rb1 mutations.20  Based on the data above, screening for Rb1 mutations 
will not be required for enrollment in this study for patients with medulloblastoma and 
ATRT as well as DIPG. About 30% of supratentorial PNETs have been noted to have p16 loss 
(7/21) and may therefore respond to a CDK 4/6 inhibitor.1 In addition, about 25% have been 
reported to harbor CDK/Cyclin D amplification.2 
There is suggestion in the literature that germ-cell tumors may be sensitive to CDK inhibition 
including CDK4/6.3,4 Mature teratomas express high levels of phospho Rb1 (pRb1) in their 
epithelial components.4 A prolonged PR was observed in an adult patient with a recurrent germ 
cell tumor treated in the Phase I study with PD-0332991.3  Three adult patients with growing 
teratomas (with strong nuclear expression of pRb1) had either sustained PR (one patient) or 
stable disease (2 patients) following treatment with the CDK 4/6 inhibitor PD-0332991.4 
 
2.2 
PD-0332991 
Specificity for CDK4/6  
PD-0332991 (Pfizer Corporation, USA) is a pyrido [2, 3-d] pyrimidin-7-one (Figure 2) and an 
orally active, water soluble, cell-permeable highly specific inhibitor of CDK4 and 6.21 The IC50 
value for both CDK4 and CDK6 is between 0.009-0.015M and >10 M for 274 other protein 
kinases including CDK2.22 PD-0332991 works by competing for ATP-binding sites on the 
enzyme.23 The mean plasma half- life of the drug is about 26 hours.3,22,24 The drug is moderately 
protein bound with unbound fraction in human plasma of 12-19%.  
 
Figure 2: Structure of PD-0332991 
 
2.2.1 Pre-clinical Studies of PD-0332991 
PD-0332991 has undergone extensive pre-clinical testing for toxicity and efficacy. Pivotal 3-
week toxicologic studies in rats identified 300 mg/m2 as the dose that produced severe toxicity 
(mostly myelosuppression and testicular degeneration) in 10% of rats.22 The maximum tolerated 


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dose of the drug in rats was 150 mg/day for 14 days. Dogs appeared to suffer more 
myelosuppression and testicular degeneration than rats.22 (See section 2.2.2.1) 
 
Following an oral dose of [14C] PD-0332991, radioactivity levels were consistently greater in 
peripheral tissue than in blood including brain, meninges, pituitary gland, choroid plexus, and 
CSF. In vitro studies using pooled human liver microsomes demonstrate a low potential of PD-
0332991 to inhibit cytochrome P450 enzymes including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 
and 2D6, based on IC50 values >30 μM. No significant induction of either CYP3A4 or CYP1A2 
in Fa2N-4 cells was observed at PD-0332991 concentrations of 0.78 and 6.25 μM (349 and 2790 
ng/mL), suggesting low potential for PD-0332991 to induce CYP3A4 and CYP1A activities at 
clinically relevant concentrations (0.19 μM or 86 ng/mL). 
 
The ability of cytochrome P450 enzyme to metabolize PD-0332991 was evaluated by incubation 
of PD-0332991 (6 μM) with the 5 major cytochrome P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 
and 3A4). CYP3A4 was the only enzyme that metabolized PD-0332991. Concordantly, 
metabolism of PD-0332991 (6 μM) in human liver microsomes was significantly reduced (>80% 
decrease) in the presence of the CYP3A4 enzyme-specific inhibitor ketoconazole (1 μM). These 
data indicate that in vitro, CYP3A enzyme mediated oxidative pathway is primarily responsible 
for PD-0332991 metabolism. After oral administration of PD-0332991 to human subjects, 
sulfonation of parent drug constituted another major clearance pathway. In vitro, SULT 2A1 was 
found to be the predominant enzyme involved in the sulfonation of PD-0332991, with potential 
for minor contributions from other SULT isoforms.  
2.2.2 Pre-clinical evidence of anti-tumor efficacy of PD-0332991 
Several in vitro and in vivo studies in solid tumor xenografts have demonstrated efficacy of 
PD-0332991 in tumors that express wild type Rb1. The latter, not surprisingly, is a pre-requisite 
for efficacy of this agent. Of the known 16 phosphorylation sites on Rb1 protein, Ser780 and 
Ser795 are the 2 sites phosphorylated by CDK4/6 and represent a biomarker for inhibition of 
CDK4/6 by PD-0332991.21,24  A panel of solid tumor cell lines including breast cancer and 
colorectal cancer21 showed significant reversible inhibition of Rb1 phosphorylation at these two 
sites that peaked at 16 hours and began to return to baseline 2 hours after drug removal (Figure 
3) with an IC50 of 0.066 μmol/L  for MDA-MB-435 breast carcinoma cells.21 At an optimal dose 
of 150 mg/kg daily for 14 days given by gavage after flank tumor implantation had reached a 
size of 100-150 g, the drug caused significant suppression of Rb1 phosphorylation in vivo, 
decreased cell proliferation, G-1 arrest (as measured by flow cytometry), and tumor regression or 
disease stabilization in a variety of adult solid tumor xenografts.21 In a colorectal carcinoma 
(Col-205) tumor, treatment initially resulted in significant tumor shrinkage (Figure 4). When 
tumors regrew after drug withdrawal, they were re-harvested and implanted in naïve mice. 
Retreatment with PD-0332991 at the same dose caused tumor regression (Figure 5) 
suggesting that initial tumor growth after stopping drug was not due to acquired 
resistance. None of the animals died due to toxicity and the maximum tolerated dose of PD-
0332991 was 150 mg/kg/day. 
 


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Figure 3 
Figure 4 
 
Figure 5 
                           
 
 
 
 
 
 
 
 
Michaud et al. investigated the efficacy of PD-0332991 in 21 GBM cell lines and xenografts 
with either intact or homozygously deleted Rb1 protein and at least one defect in the 
CDK4/6/cyclin D/ink4B signaling pathway.25 Similar to what has been described with other 
solid tumor xenografts, treatment of cell lines and intracranial xenografts resulted in a 
predictable decrease in Rb1 phosphorylation, proliferative rate (Figure 6), G-1 arrest, and 
apoptosis that was dose dependent and occurred only in Rb1 proficient cell lines and xenografts 
and significant tumor regression (Figure 7).25 In addition, Rb1 depletion using siRNA resulted in 
abrogation of PD-0332991 activity.25 Also, the study demonstrated that the drug penetrated 
the blood-tumor barrier efficiently (Figure 8). Synergistic effect could be demonstrated by 
combining radiotherapy and Temozolomide with PD-0332991.25 
 


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Figure 6: PD 0332991 decreases 
proliferative rate in GBM 
 
 
Figure 7: PD 0332991 causes significant tumor 
regression of IC GBM xenograft with improved 
survival 
 
Figure 8: PD0332991 penetrates well 
into tumor as compared to brain 
around tumor (BAT) or opposite 
hemisphere 
 
 
In another study of intracranial malignant glioma xenografts that were derived from 
DBTRG05-MG astrocytoma cell line harboring BRAFV600E mutation and INK4a-ARF deletion, 
treatment with PLX4720 (a BRAFV600E inhibitor) and PD-0332991 extended survival additively 
compared to either drug alone (Figure 9).26 
 
 
Figure 9: SCID mice with intracranial malignant glioma xenografts derived DBTRG05-
MG astrocytoma cell line (harboring BRAFV600E and INK4a-ARF deletion) with histologic 
appearance, nestin expression, and high KI-67 (A). Treatment with PLX4020 or PD 


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0332991 results suppression of tumor growth but the combination significantly 
outperforms monotherapy (B) and better prolongation of survival (D) and decreased 
proliferation rate (D). In comparison, treatment of IC xenografts from GS2 malignant 
glioma cell line (wild type BRAF and Intact Ink4-ARF) shows no change in tumor growth 
or survival with either mono or combination therapy 
 
PD-0332991 has also been tested in brain stem glioma animal models. Aoki et al., have shown 
that treatment of a brainstem glioma xenograft model with PD-0332991 provides significant 
survival benefit relative to vehicle-treated mice.27 In addition, the Becher laboratory is carrying 
out preclinical studies with PD-0332991 in a genetically engineered brainstem glioma mouse 
model that is driven by PDGF overexpression and Ink4-ARF loss. In a proliferation assay, the 
IC50 of cells derived from the Ink4a-ARF deficient PDGF-driven brainstem glioma model was 
2M as compared to > 5M for cells derived from a p53 deficient PDGF-driven brainstem 
glioma. Two daily doses of PD-0332991 given by gavage to brainstem glioma-bearing mice 
significantly inhibited tumor cell proliferation as measured by pH3 demonstrating good drug 
delivery across the blood-brain-barrier. 
 
Dr. James Olson at the Fred Hutchinson Cancer Center in Seattle, WA has treated mice 
implanted with patient derived medulloblastoma flank xenografts with PD-0332991 at 150 
mg/kg/day for 14 days (Olson J, Seattle, WA; personal communication 2013). Significant tumor 
regressions (Figure 10) were observed associated with decrease in proliferation rate (Figure 10), 
Rb1 phosphorylation (Figure 12) and improvement in animal survival (Figure 11) compared to 
vehicle alone. Maintenance of therapy past 38 days of initial treatment resulted in persistent 
tumor control suggesting that tumors do not develop drug resistance. Decreasing dose to 75 
mg/kg/day did not result in loss of efficacy (Figure 11).  
 
 
 
Figure 10: Medulloblastoma flank xenografts in mice treated with vehicle or PD0332991 
(150 mg/kg/day for 14 days) 
 


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Figure 11: Survival of mice with Medulloblastoma flank tumors treated with vehicle or PD 
0332991 
 
 
Figure 12: Western blot to demonstrate decrease in RB phosphorylation following 
treatment with PD-0332991 (Lanes 3, 4, and 5) compared to vehicle (lanes 1 and 2). Tumor 
from mouse in lane 5 was sacrificed at 24 hours as compared to 4 hours for those on lane 3 
and 4. 
 
Dr. Olson has similarly used an Atypical Teratoid Rhabdoid Tumor (ATRT) flank xenograft 
to demonstrate the efficacy of PD-0332991 in this tumor type. As in the medulloblastoma model, 
treatment with PD-0332991 at a dose of 150 mg/kg/day for 14 days resulted in excellent tumor 
regression and prolongation of survival of animals receiving the drug as compared to vehicle 
controls. Tumors treated with PD-0332991 showed decreased proliferation rate and Rb1 
phosphorylation.  
2.2.2.1  Animal Toxicity 
Results of animal toxicity studies in this section have been obtained from the Investigator’s 
Brochure and have not been published yet. Pivotal toxicity studies were performed in rats and 
dogs. The latter animal was chosen due to the drug’s better bio-availability in this species than in 
non-human primates. The predominant toxicities were related to bone marrow, lymphoid, and 
testicular tissues. In the pivotal 3-week toxicity study, deaths occurred at a dose of 1200 mg/m2 
and 2400 mg/m2 given once daily for 3 weeks in male and female rats respectively. Death 
occurred in dogs at > 200 mg/m2 daily for 2 weeks. Reversible bone marrow suppression 
(especially neutropenia) and lymphoid depletion (mesenteric lymph node, spleen, and thymus) 


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were observed in rats (males > females) at doses of > 300-1200 mg/m2. Decrease in 
reticulocytes, neutrophils, and monocytes were observed within one week of treatment with 
variable nadir times and recovery within 2 weeks of cessation of therapy. In dogs, similar 
changes were observed at doses > 12mg/m2 and nadir time was typically seen at the end of the 
dosing period (day 21).   
 
Irreversible testicular degeneration occurred in rats at > 300 mg/m2 and dogs at > 12 mg/m2. 
There was decrease in spermatocytes in the spermatogenic epithelium and associated with 
decrease in testicular weight that was related to the administered dose. These findings are 
consistent with CDKs and cell cycle proteins being involved in the normal tissue of the bone 
marrow, lymphoid organs, and testis indicating the rapid turnover of cells in these compartments.  
In another study, PD-0332991 was administered by oral gavage to Sprague-Dawley rats at doses 
of 0, 10, 30, and 100 mg/kg/day in males and 0, 50, 100, and 300 mg/kg/day in females 
(20/sex/group; 15/sex/group in main and 5/sex/group in recovery) on an intermittent dosing 
schedule (7 cycles of treatment where each cycle consisted of 3 weeks of continuous daily 
dosing followed by a 1-week non-dosing period) for 27 weeks. Animals were evaluated by 
indirect ophthalmoscopy pre-dose and by indirect and slit lamp ophthalmoscopy prior to 
termination (within 7 days prior to scheduled necropsy). Slit lamp ophthalmoscopy was included 
for a more accurate assessment of ocular changes that were observed through indirect 
ophthalmoscopy. Indirect ophthalmoscopy results revealed a degraded view of the fundus and 
the presence of cataracts in high dose males (100 mg/kg/day) that had normal fundus 
examinations prior to the start of the study. Cataracts (anterior cortical, incomplete, and 
complete) were identified by slit lamp ophthalmoscopy in male rats at ≥ 30 mg/kg/day with 
dose-related severity (Table 1), but not in females at any dose tested (300 mg/kg/day). 
 
Table 1: Slit Lamp Ophthalmoscopy 
 
 
 
Lens degeneration was observed microscopically with dose-related incidence and with minimal 
to moderate severity in males at ≥ 30 mg/kg/day and minimal severity in males at 10 mg/kg/day 
and females at ≤ 100 mg/kg/day (not identified in females at 300 mg/kg/day) (Table 2). Among 
the animals that have been evaluated microscopically, lens degeneration was identified in all 
animals that were noted to have cataracts on slit lamp examination. 
 


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Table 2: Microscopic examination of the eyes 
 
 
 
The identification of cataracts in rats following 27-weeks of intermittent dosing represents new 
target organ toxicity. In the previous rat and dog repeat-dose toxicity studies up to 15 weeks 
duration, the primary target organ findings were observed in the hematolymphopoietic and male 
reproductive tissues. There were no PD-0332991-related ocular toxicities at doses up to 200 and 
2 mg/kg/day in rats and dogs, respectively, in the 15-week toxicity studies (unbound systemic 
AUC exposures of 5200 and 684 ng•h/mL, respectively). In addition, no cataracts have been 
identified in PD-0332991-treated dogs at doses up to 3 mg/kg/day following 27-weeks of 
intermittent dosing (equivalent duration to that at which cataracts were observed in the rat study) 
using slit lamp ophthalmoscopy in an ongoing 39-week repeat-dose oral toxicity study (Study 
8282225; Sponsor Reference Number 13LJ037; exposure data not available). 
 
A no observed effect level has not been identified for cataract formation from the 27-week rat 
toxicity study, based on the histological presentation of lens degeneration. The available data 
suggests that the lens degeneration observed at the lowest doses in both male and female rats is 
PD-0332991-related. Day 189 systemic AUC (total) exposure was 6000 ng•h/mL (750 ng•h/mL, 
unbound, based on Fu of 0.125 in the rat) and 2650 ng•h/mL (331 ng•h/mL, unbound) in males 
at 10 mg/kg/day and females at 50 mg/kg/day, respectively. These exposures are comparable to 
clinical exposure at the recommended human dose of 125 mg QD (unbound AUC 301 ng•h/mL). 
The mechanism for cataract formation in PD-0332991-treated rats is unknown; however, its 
pathogenesis may be related to primary pharmacology. CDK4 expression (mRNA and protein) 
has been identified in the lens epithelial layer and in lens fibers of rats, suggesting its importance 
to lens differentiation. Altered cell growth of the lens epithelium is also recognized as a potential 
mechanism for cataract formation. 
 
In addition to the above toxicities, pulmonary toxicities of rales and dyspnea were observed in 
rats given oral doses > 300 mg/m2. Histopathologic examination revealed accumulation of foamy 
alveolar macrophages and tracheal mucosal atrophy. In dogs, apnea occurred following 
intravenous (i.v) administration of PD-0332991 at a dose of 5 mg/kg that was attributed to 
central respiratory depression compounded by the effects of propofol induced general anesthesia.  
The in vitro Purkinje fiber and human ether -a-go-go (hERG) assays along with cardiovascular 
study in dogs given doses over 10 mg/kg indicate a risk for QT-interval prolongation. The IC20 in 
the hERG assay was 1 μM (447.5 ng/mL) and QT prolongation occurring dogs was associated 
with a Cmax > 211 ng/mL. No effects on ECG parameters were noted in dogs given 2 mg/kg in 3- 
or 15-week toxicity studies, with unbound Cmax values (80 and 42 ng/mL respectively) that 


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exceeded those associated with human clinical dose of 125 mg QD (18 ng/mL).  
 
2.2.2.2  Pre-clinical Pharmacology 
PD-0332991 was given via oral and i.v routes to Sprague-Dawley rats, Beagle dogs, and 
Cyanomolgus monkeys. The PK parameters following single dose administration are given in 
Table 3. In general, mean plasma clearance values were low to moderate in all species and 
volume of distribution at steady state was about 10 fold greater than total body water indicating 
drug distribution into peripheral tissues. 
 
Table 3 
 
 
PK parameters following multiple dosing of PD-0332991 in the same species is given in Table 4. 
 
The Cmax and AUC values increased in a dose-related manner in all species. There was gender 
related differences in rats (higher rates of clearance in females compared to males). Dose 
accumulation (3-fold) was observed following multiple dosing both rats and dogs. 
 
 


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Table 4 
 
 
2.2.3 Adult Clinical Trials 
 
2.2.3.1 Phase I trial of PD-0332991 in adults with recurrent solid tumors 
PD-0332991 has been tested in a Phase I trial in adults with recurrent solid tumors and 
lymphomas (A5481001) that explored two different schedules of the drug. In the first schedule  
reported by Schwartz et al., adult patients with Rb1 positive recurrent solid tumors were enrolled 


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across four cohorts using doses of 100 mg, 150 mg, 200, and 225 mg given orally daily for 14 
days every 3 weeks (Schedule 2/1).3 No DLTs were observed at the 100 mg or 150 mg dose 
level. Dose limiting myelosuppression occurred in 2/3 patients at the 225 mg dose level [Grade 
IV neutropenia and thrombocytopenia (n=1) and Grade III neutropenia with delayed recovery 
(n=1)]. An intermediate dose of 200 mg/day was chosen. After only one DLT was observed 
(Grade III neutropenia and thrombocytopenia) in 6 enrolled patients at this dose, the cohort was 
expanded to a total of 20 patients. Three additional patients suffered DLT (Grade III 
myelosuppression with delayed recovery) with an overall 20% rate of DLT at this dose level. 
Since this did not exceed the preset limit of 33%, 200 mg/day for 14 days every 4 weeks was 
declared the MTD. Additional toxicities were mild and included Grade I fatigue and Grade I-II 
diarrhea. No patient had Grade 3 prolongation of QTc interval on EKG during therapy. Plasma 
PK studies revealed a dose proportional increase in Cmax and AUC0-10 on days 1 and 8. In 
samples obtained from patients receiving 200 mg q daily, repeated dosing led to steady state 
levels. The median Tmax was 4.2 hours and volume of distribution was 3241 liters (more than the 
adult total body water of 42 liters) suggesting extensive tissue penetration. PD-0332991 was 
eliminated slowly with a mean T1/2 of 26.7 hours.21 One patient with a non-seminomatous germ 
cell tumor of the testis achieved a prolonged partial response and 9 had SD. Six patients with SD 
had treatment for ≥ 4 cycles and 2 for ≥ 10 cycles.  
 
In the second schedule of the same Phase I study, daily treatment for 21 days every 4 weeks 
(Schedule 3/1) was evaluated in 41 adult patients with recurrent Rb1 positive solid tumors.22 
Dose levels studied included 25, 50, 75, 100, 125 and 150 mg orally once daily. Five DLTs 
(either Grade III or IV neutropenia) were observed; 2 at 75 mg, 1 at 125 mg, and 2 at 150 mg. 
Thus 125 mg was declared the MTD. In an expanded cohort of 22 patients at this dose level, only 
2 additional patients suffered Grade III neutropenia, making this the recommended Phase II dose. 
Additional toxicities were mild and included nausea, fatigue, and diarrhea. There was only one 
instance of a mild QTc prolongation in one patient that was felt not related to study drug.   
Plasma PK study results were similar to the previous Phase I trial. 
 
2.2.3.2 Phase II trial of PD-0332991 in adults with recurrent mantle cell 
lymphoma and breast cancer 
 
A Phase II trial of PD-0332991 was recently reported in adults with recurrent mantle cell 
lymphoma (a tumor that has aberrant cyclin D1 expression and homozygous loss of CDKN2A 
and hence dysregulation of the cell cycle signaling pathway).24 Seventeen patients (median age, 
66 years) were treated with PD-0332991 at 125 mg orally once daily for 21 days every 4 weeks 
until disease progression or unacceptable toxicity. The treatment was well tolerated and most 
Grade III or IV events were neutropenia or thrombocytopenia. No patient came off study for 
toxicity. The objective response rate was 18% (PR 2, CR 1) in 16 evaluable patients. An 
additional 7 patients experienced stable disease. Objective responses were observed between 4-8 
cycles. Three patients have had prolonged stable disease on treatment between 565 – 903+ days.  
Five patients received study drug for more than one year. Six patients suffered PD. Evaluable 
lymph node biopsies in 10 paired tumor samples (done before and after 21 days of treatment) 
showed significant reduction of phosphor-RB (pS807/811) [mean, 89% (range, 51.6-100)] 
although total Rb1 staining was preserved. There was also similar reduction of Ki-67 staining 
(mean, 78%, range, 5-98.2%). Degree of reduction of phosphor-RB correlated with that of Ki-67. 


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All patients had Fluoro-deoxy glucose (FDG) PET and Fluoro-thymidine (FLT) scans at baseline 
and demonstrated avid tumor uptake of both FDG and FLT. Sixteen patients had both a baseline 
and post-treatment scans (day 21) for evaluation. The 3 patients who had objective responses 
demonstrated significant reduction (> 80%) of FLT uptake and a 24% decrease in FDG. Even 
patients who had SD or PD by routine imaging demonstrated > 25% reduction in both PET 
studies.24  
 
In a randomized Phase I/II trial of PD-0332991 in combination with letrozole vs. letrozole alone 
as first-line treatment in 165 post-menopausal women with  ER+/HER2- advanced breast cancer, 
preliminary analysis of median progression-free survival (PFS) was significantly higher in 
patients receiving PD-0332991 plus letrozole vs. letrozole alone (26.2 vs. 7.5 months 
respectively) with a hazard ratio (HR) = 0.32 (95% CI 0.19-0.56).28 The most commonly 
reported treatment-related adverse events included neutropenia, leucopenia, anemia, and fatigue. 
 
2.2.3.3 Pharmacology/Pharmacokinetics 
 
Pharmacokinetic data of PD-0332991 is available from Phase I and II studies done in adults 
(n=137) with recurrent solid tumors. On Day 1, all patients had detectable plasma concentrations 
of PD-0332991 at the first measured time point (1 hour) following oral administration. The 
exposure (AUC(0-10) and Cmax) increased in a dose-proportional manner over the dose range of 
25-225 mg QD following PD-0332991 administration on Days 1 and 8 of Cycle 1, although 
some variability (low to moderate) around these doses was observed particularly at the 150 mg 
QD dose level. Following repeated daily dosing to Day 14 and Day 21 (assumed to be steady-
state), PD-0332991 was absorbed with a median Tmax of ~4 hours (Table 5). The mean PD-
0332991 Vz/F was 3103 L, which is significantly greater than total body water (42 L), indicating 
that PD-0332991 extensively penetrates into peripheral tissues. PD-0332991 was eliminated 
slowly; the mean t½ was 26.5 hours and the mean CL/F was 86.1 L/hour. PD-0332991 
accumulated following repeated dosing with a median Rac of 2.4, which is consistent with a half-
life of ~27 hours. Renal excretion of PD-0332991 was a minor route of elimination with ~1.7% 
of the drug excreted unchanged in urine over the 10-hour collection period in the 125 mg and 
200 mg dose group, combined.  No dose adjustment is required for patients with mild, moderate 
or severe renal impairment (creatinine clearance [CLCR] 15 mL/min). Insufficient data are 
available in patients requiring hemodialysis to provide any dosing recommendation in this 
patient population. PD-0332991 is primarily metabolized by the liver and eliminated via feces.. 
Studies suggest that no dose adjustment is required for patients with mild or moderate hepatic 
impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-
Pugh class C), dose reduction is warranted. 
 
 
 
 
 
 
 
 
 


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Table 5 
 
 
Final pharmacokinetic data are available from 24 healthy male volunteers from Protocol  
A5481009. This was an open-label, randomized, 4-period, 4-treatment, 4-sequence, crossover, 
single-dose study employing administration of 4 PD-0332991 formulations in the fasted state to 
healthy adult volunteers. The primary objectives of the study were to identify a formulation that 
is bio-equivalent with the isethionate formulation used in the Phase 1-2 studies for use in phase 3 
studies, and to explore the pharmacokinetics of the PD-0332991 active lactam metabolite, PF-
05089326, following single oral doses of PD-0332991. Each subject received 4 single oral doses 
of PD-0332991 as 4 distinct formulations (Treatments A, B, C and D) separated by a washout 
period of at least 10 days. Treatments A (Reference), B, C, and D were single oral doses of PD-
0332991 125 mg isethionate capsule; freebase small particle capsule; freebase large particle 
capsule and 50 mg oral solution, respectively. 
 
Plasma PD-0332991 PK parameters are summarized descriptively in Table 6.  The mean 
apparent t½ of PD-0332991 was similar for each of the 4 treatments with mean values ranging 
from 22.4 to 22.7 hours. Variability for PD-0332991 AUCinf, AUClast and Cmax was somewhat 
higher for the freebase small and large particle capsule formulations (Treatments B and C) 
compared to the isethionate capsule and oral solution formulations (Treatments A and D), with 
CV% values in the range of 22% to 48% for AUCinf and AUClast combined and 24% to 58% for 
Cmax, respectively. 
 


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Figure 13: Median Plasma PD-0332991 concentration-time profiles following single oral 
doses of PD-0332991 Study A5481009 
 
 
 
Table 6: Summary of Plasma PD-0332991 PK parameters following single doses of 
Treatment A, B, C and D (Study A5481009) 
 
The results for statistical comparisons of the Test treatments relative to the Reference treatment 
(Treatment A) are summarized in Table 6. PD-0332991 freebase large particle capsule 
(Treatment C) prepared with an API lot with large particle size was shown to be bio-equivalent 
to the PD-0332991 isethionate hard capsule IR formulation (Treatment A) with respect to 
adjusted geometric mean ratios (90% CIs) of AUCinf, AUClast and Cmax using pre-determined 


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equivalence limits of 80% to 125%.  Therefore, the freebase large particle size (API) capsule will 
be used in this trial. The preliminary results from the recently performed food-effect study 
(“A5481021, a Phase 1, open-label 4 sequence 4 period crossover study of PD-0332991 in 
healthy volunteers to estimate the effect of food on the bioavailability of PD-0332991”) has 
provided evidence that when a single 125 mg dose of PD-0332991 as administered under fed 
conditions (including high fat or low fat meal given together with PD-0332991, or moderate fat 
meal given 1 hour before and 2 hours after PD-0332991) as a freebase formulation the PD-
0332991 exposure levels were more uniform across the population than when taken in the fasting 
condition. The preliminary data from the A5481021 food-effect study indicated that there was no 
clinically significant increase in PD-0332991 drug exposures when a freebase formulation of 
PD-0332991 was administered with food when compared to administration in the fasted state. 
The safety profile of the drug should remain unchanged in the presence of food. A small 
percentage of subjects who take PD-0332991 in the fasted state may experience variable drug 
exposures, and administration of PD-0332991 with food can make drug exposure in these 
subjects more uniform with the population. 
 
2.3 
Rationale 
2.3.1 Rationale for version 2.0 
Survival for children with recurrent CNS tumors is dismal and novel therapeutic options need to 
be developed in order to improve outcome. Cancer initiation and progression is dependent on 
deregulation of the components and phases of the cell cycle. Ample evidence exists (see 
background section) on alterations of CDKs, Cyclins, cell cycle inhibitors, and checkpoint 
proteins in pediatric CNS tumors. The presence of specific mutations in the proteins involved in 
G1-S phase transition of the cell cycle in these tumors is particularly relevant for the use of a 
specific CDK4/6 inhibitor like PD-0332991. Furthermore, it is likely that over 60% of pediatric 
CNS tumors are likely to have intact Rb-protein, a pre-requisite for the efficacy of this cell cycle 
inhibitor. PD-0332991 has not been tested in children with cancer thus far. A Phase I study is 
therefore needed to assess the toxicity, MTD, pharmacokinetics, and preliminary evidence of 
efficacy of this agent in this patient population. Since myelosuppression is the predominant side 
effect of this agent, the Phase I study will first evaluate the toxicities in children who have not 
been heavily pre-treated previously. Once MTD has been established in this cohort of patients, 
consideration will be given to expanding the trial to include those who have received intensive 
cytotoxic therapy including myeloablative chemotherapy +/- craniospinal irradiation. In addition, 
only patients who have no evidence of cataract formation on ophthalmologic examination will be 
eligible for this study based on pre-clinical evidence of development of cataracts and lens 
degeneration in rats treated with PD-0332991 on a 21-day cycle at doses > 30 mg/kg/day for 27 
weeks.  
2.3.2 Rationale for Amendments  
Version 3.0 
The purpose of Amendment Version 3.0 was to update CAEPR based on the February 2015 IB.  
 
Version 4.0 
Since myelosuppression was the DLT in adult patients with recurrent solid tumors treated with 
PD-0332991, the current PBTC-042 study was open only to patients who had either focal RT 


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and/or < 2 prior myelosuppressive chemo or biologic therapy regimens (stratum I) and three dose 
levels tested; dose level 1 (50 mg/m2/day), dose level 2 (75 mg/m2/day), and dose level 3 (90 
mg/m2/day). Treatment was given daily for 21 days with a week of rest (one course = 28 days). 
Dosing was based on BSA calculated at the beginning of each course. Enrollment to Stratum I is 
currently ongoing and has accrued 12 patients at dose levels 1 (n=3), 2 (n=3), and 3 (n=6). Two 
patients enrolled at dose level 3 were not evaluable for DLT. Of the 10 patients evaluable for 
DLT, 2 of 4 at dose level 3 experienced grade 4 neutropenia as their DLT. Hence the MTD was 
exceeded at dose level 3, and 3 additional patients have been enrolled at dose level 2. The MTD 
for stratum I is expected to be 75 mg/m2/day for 21 days.  
 
With the MTD identified in less-heavily pre-treated patients (stratum I), this phase I study will be 
expanded to include heavily pre-treated patients (defined as those who have received more than 4 
prior regimens (either myelosuppressive chemotherapy or biologic) ± craniospinal irradiation ± 
myeloablative chemotherapy plus stem cell rescue) in a separate cohort (stratum II). Treatment 
of these patients will be initiated at 50 mg/m2/day (one dose level below the potential MTD in 
stratum I) as the starting dose level. Stratum II is likely to mostly include patients with recurrent 
medulloblastoma, other central PNETs, ATRT, and germ cell tumors. Recent genomic studies of 
medulloblastoma and ATRT have demonstrated that Rb1 protein is intact in these tumors.18-20 
Therefore, patients with medulloblastoma or ATRT will not be required to have their tumors 
screened for Rb1 expression.  
 
2.3.3 Rationale for version 5.0 
Per the recommendation from Pfizer, Cerebrospinal Fluid Pharmacokinetic Studies have been 
removed in Version 5.0 due to the high rates of non-specific binding of PD-0332991 to 
collection syringes/tube/vials/etc. when collected in media with low protein content (i.e. CSF). 
 
2.3.4 Rationale for version 6.0 and 7.0 
The purpose of Amendment Version 6.0 was to update CAEPR based on the December 2015 IB.   
The amendment version 7.0 was mainly due to the change of the protocol title because of a 
change in a drug supply of PD-0332991 from Pfizer to a commercial agent IBRANCE. The 
Principal Investigator and the IND Sponsor information were updated to Dr. David Van Mater.  
 
2.3.5 Rationale for version 8.0 
The protocol has been amended to reflect new and/or modified risk information for palbociclib 
(PD-0332991) based on the March 2017 IB.  Additionally, language was added to clarify results 
of PK studies conducted in patients with renal and hepatic impairment as reflected in the July 
2017 Investigator’s Brochure. 
 
2.4 
Correlative Studies Background 
2.4.1 Rationale for Biology Studies 
2.4.1.1  Hypothesis:  
To evaluate CDK4/6, cyclin D1-3, Ink4a-ARF copy-number variations in available tumor tissue 
by array comparative, genomic hybridization (aCGH).  
2.4.1.2  Clinical Data 
Recent studies on the genomic aberrations of pediatric CNS tumors have demonstrated that a 
subset harbor focal gains in CDK4, CDK6, Cyclin D1-3, or homozygous Ink4a-ARF loss 


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suggesting that patients with these tumors may benefit from therapies targeting CDK4/6. About 
35% of pediatric brainstem gliomas harbor focal gains in CDK4, CDK6, or Cyclin D1-3.9 About 
20% of pediatric brainstem gliomas have been shown to have p16 loss.10 Homozygous Ink4a-
ARF loss is seen at the genomic level in 20% of non-brain stem gliomas.12 In addition focal gain 
in CDK6, CDK4, and Cyclin D2 is observed in up to 6% in these tumors.12,13 In pilocytic 
astrocytomas (PA), the most common subtype of pediatric CNS tumors, a subset of patients with 
poor prognosis harbor p16 loss (13.6% or 9/66), suggesting that some recurrent PAs may 
respond to CDK4/6 inhibitor.14 Homozygous CDKN2A (the gene for p16) deletions have been 
observed to be a poor prognosis marker in ependymoma.15 CDK6 is overexpressed in 30% of 
medulloblastomas. Overexpression of CDK6 correlates significantly with poor prognosis and 
represent an independent prognostic marker of overall survival on multivariate analysis (P = 
0.02).17 About 30% of supratentorial PNETs have been noted to have p16 loss (7/21) and may 
therefore respond to a CDK 4/6 inhibitor.1 In addition, about 25% have been reported to harbor 
CDK/Cyclin D amplification.2 
 
Based on this existing data and notwithstanding the confines of a Phase I study, it might be 
worthwhile evaluating and describing the cell cycle protein dysregulation in the tumors of 
patients who consent to have previously stored formalin fixed paraffin tumor tissue analyzed by 
aCGH. Feasibility of this approach would help us design a Phase II study in which responses 
would be correlated with alterations of specific targets within the cell cycle in patients given the 
MTD of PD-0332991 derived from this study. 
 
2.4.2 Rationale for Pharmacokinetic Studies 
Because the pharmacokinetics of this agent are relatively unknown in the pediatric population, 
this information will be essential for evaluating toxicity and disease response and for refining 
dosing in future clinical trials of PD-0332991. The results of these studies will provide the basis 
for assessing the relationship between the disposition of PD-0332991 in adult and children. 
Mandatory pharmacokinetic studies are needed to characterize the disposition of PD-0332991in 
this patient population. Insights into the biologically active dosage will be gained by relating PD-
0332991systemic exposure (e.g., AUC) to results of pharmacodynamic studies (e.g., percentage 
change in ANC and platelets compared to baseline). 
 
In vitro studies indicate that PD-0332991 is a substrate of CYP3A4, and dexamethasone is a 
known inducer of CYP3A4. Thus, one might expect lower exposures of PD-0332991 when 
administered concurrently with dexamethasone. Indeed, following multiples doses of PD-
0332991 in A5481004 Phase 2 (dosing Schedule B), the mean PD-0332991 24-hr trough drug 
concentrations seem to decrease with time. The mean PD-0332991 trough concentrations on 
Cycle 1 Day 8, Cycle 1 Day 11, and Cycle 2 Day 11 were 45.33, 44.09, and 32.00 ng/mL, 
respectively, which is suggestive of a decreased PD-0332991 exposure when administered after 
dexamethasone-mediated enzyme induction has occurred. It should be noted that the exposure of 
PD-0332991 observed in this study is considerably lower compared to those observed in Studies 
A5481001 and A5481003 at the dose levels likely due to the induction effect of dexamethasone. 
Hence, patients who are receiving dexamethasone will have optional plasma PK studies done 
following discontinuation of this drug. 
 


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2.4.3 Rationale for Pharmacogenetic Studies 
PD-0332991 has been shown in-vitro and in-vivo to be a substrate for the efflux-transporter 
proteins P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2).29 
PD-0332991 is also metabolized hepatically by CYP3A4. Therefore, polymorphisms in ABCB1 
and ABCG2, which encode for P-gp and BCRP, could potentially alter inter-individual variability 
in the PD-0332991 dose-exposure-response relationships. Hence, pharmacogenetic studies will 
be included as a secondary objective. In order to examine the role of genetic variants in these 
transporters/metabolizing enzymes, genomic DNA will be isolated from peripheral blood cells to 
determine the relevant polymorphisms. We will then examine associations between these 
polymorphisms and PD-0332991 pharmacokinetic parameters. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 PATIENT SELECTION 
All subjects must meet the following inclusion and exclusion criteria.  No exceptions will be 
given. Imaging studies to establish eligibility must be done within three weeks prior to 
enrollment. All other clinical evaluations to establish eligibility must be done within 14 days 
prior to enrollment. 
3.1 
Screening Criteria 
3.1.1 Screening Consent 
Patients who are candidates for enrollment are willing to sign a screening consent and provide 
pre-trial tumor material for Rb1 testing. Screening applies to patients with all types of CNS 
tumors except DIPG, medulloblastoma, or ATRT.  
3.1.2 Tumor 
Patients must have recurrent, progressive or refractory central nervous system (CNS) tumors. 
Patients with secondary malignant gliomas will be eligible for this study but should conform to 
the strict prior treatment exposure criteria irrespective of the number of individual tumors treated 
previously. Patients with low grade gliomas are excluded.  
3.1.3 Prior Therapy  
Stratum I: Less-Heavily Pretreated Stratum 
• Patients who  have received the following:  
i. ≤  4 prior treatment regimens* with either myelosuppressive chemotherapy or biologic 
agents and/or  
ii. focal radiotherapy  
 
Stratum II: Heavily Pretreated Stratum 
• Patients who have received ANY one of the following 3 criteria: 
i. 
> 4 prior treatment regimens* with either myelosuppressive chemotherapy or biologic 
agents and/or 
ii. craniospinal irradiation and/or 
iii. myeloablative chemotherapy with autologous stem cell rescue  
 
*A treatment regimen is defined as a single agent (chemotherapeutic or biologic), or a sequential 
combination of therapies that can include radiotherapy (with or without concurrent 
radiosensitizer, chemotherapy, or biologic therapy) followed by maintenance therapy (either 
single or combination) given over a period of time at either diagnosis or relapse. 
 
3.1.4 Age 
Patient must be ≥ 4 years and ≤ 21 years of age.   
3.1.5 Patient must be able to swallow capsules.  
3.1.6 Pre-Trial Tumor Tissue availability 
Formalin fixed paraffin embedded tumor tissue (preferably from the most recent recurrence) 
must be available to assess Rb1 protein status prior to enrollment. Only patients with recurrent 
diffuse intrinsic brain stem glioma (DIPG), medulloblastoma, or ATRT can be enrolled without 
the need for available tumor tissue for Rb1 protein status confirmation.  


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3.1.7 BSA: 
• Patients enrolled on dose level 1 (50mg/m2) must have BSA≥ 1.20m2 
• Patients enrolled on dose level 2 (75mg/m2) must have BSA≥0.93m2 
• Patients enrolled on dose level 3 (95mg/m2) must have BSA≥0.70m2 
 
3.1.8 Potential Eligibility for Study Enrollment 
Patients screened for this trial should be expected to meet the criteria for treatment. 
 
3.2 
Eligibility for Treatment Criteria 
 
3.2.1 Eligible Diagnosis 
 
Tumor type: 
Histologically confirmed retinoblastoma protein (Rb1) positive primary recurrent, progressive, 
or refractory central nervous system tumors. Patients with low grade gliomas are excluded.  
 
Formalin fixed paraffin embedded tumor tissue (preferably from the most recent recurrence) 
must be available to assess Rb1 protein status prior to enrollment. Patients with recurrent diffuse 
intrinsic brain stem glioma (DIPG), medulloblastoma, or ATRT can be enrolled without the need 
for available tumor tissue for Rb1 protein status confirmation.  
 
3.2.2 Measureable Disease 
Patients must have measurable disease (in 2-dimensions) on MRI scan of brain and/or spine to 
assess preliminary evidence of response. 
3.2.3 Age 
Patient must be ≥ 4 years and ≤ 21 years of age at the time of enrollment. 
3.2.4 BSA: 
• Patients enrolled on dose level 1 (50mg/m2) must have BSA≥1.20m2 
• Patients enrolled on dose level 2 (75mg/m2) must have BSA≥0.93m2 
• Patients enrolled on dose level 3 (95mg/m2) must have BSA≥0.70m2 
3.2.5 Prior Therapy  
Stratum I: Less-Heavily Pretreated Stratum 
• Patients who  have received the following:  
i. 
≤  4 prior treatment regimens* with either myelosuppressive chemotherapy or 
biologic agents and/or  
ii. 
focal radiotherapy.   
 
Stratum II: Heavily Pretreated Stratum 
• Patients who have received ANY one of the following 3 criteria: 
i. 
> 4 prior treatment regimens* with either myelosuppressive chemotherapy or biologic 
agents and/or 
ii. 
craniospinal irradiation and/or 
iii. 
myeloablative chemotherapy with autologous stem cell rescue  
*A treatment regimen is defined as a single agent (chemotherapeutic or biologic), or a sequential 


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combination of therapies that can include radiotherapy (with or without concurrent 
radiosensitizer, chemotherapy, or biologic therapy) followed by maintenance therapy (either 
single or combination) given over a period of time at either diagnosis or relapse. 
 
Patients must have fully recovered from the acute treatment- related toxicities of all prior 
therapies prior to entering this study. For those acute baseline adverse events attributable to prior 
therapy, patients must meet organ function criteria (section 3.2.10) in the Inclusion and 
Exclusion Criteria. 
 
3.2.5.1 Chemotherapy: Patients must have received their last dose of 
known myelosuppressive anticancer chemotherapy at least three (3) 
weeks prior to enrollment in the study or at least six (6) weeks for 
those receiving nitrosourea. 
 
3.2.5.2 Bone marrow/Stem Cell Infusion:  
 
≥ 3 months since autologous bone marrow/stem cell infusion prior 
to enrollment (stratum II only) 
 
3.2.5.3 Biologic therapy: Patients should have received their last dose of 
biologic agent ≥ 7 days prior to enrollment.  In the event the patient 
has received another biologic agent and has experienced ≥ Grade 2 
myelosuppression, then at least three (3) weeks must have elapsed 
prior to enrollment. If the investigational or biologic agent has a 
prolonged half-life then at least three (3) weeks interval is required. 
For patients on monoclonal antibodies including Bevacizumab, 
please refer to list of half-lives available on the PBTC webpage 
under Generic Forms and Templates. 
 
3.2.5.4   Radiotherapy:  
Patients must have had their last fraction of:  
• Focal irradiation > 2 weeks prior to enrollment  
• Craniospinal irradiation > 3 months prior to enrollment (stratum II only) 
   
3.2.5.5 Corticosteroids: Patients who are receiving dexamethasone or other 
corticosteroids must be on a stable or decreasing dose for at least 1 
week prior to enrollment. It is recommended that patients be off all 
steroid therapy or receive the least dose that will control their 
neurologic symptoms 
 
3.2.5.6 Growth factors: All colony forming growth factor(s) have been 
discontinued for at least one week prior to enrollment (filgrastim, 
sargramostim, and erythropoietin). For patients on long acting 
growth factors, the interval should be two weeks.  
 


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3.2.6 Inclusion of Women and Minorities 
Both males and females of all races and ethnic groups are eligible for this study. 
 
3.2.7 Neurologic Status 
Patients with neurological deficits that are stable for a minimum of one week prior to enrollment. 
 
3.2.8 Patients must be able to swallow capsules.  
 
3.2.9 Performance Status 
Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky Performance Score (LPS 
for ≤ 16 years of age) assessed within two weeks of enrollment must be ≥ 60. 
3.2.10 Organ Function  
Patients must have normal organ and marrow function as defined below:  
• Absolute neutrophil count >1,000/mm3  
• Platelets >100,000/ mm3  transfusion independent (no platelet transfusion one week 
prior to enrollment ) 
• Hemoglobin ≥ 8g/dl  
• Total bilirubin ≤ 1.5 times upper limit of institutional normal (ULN) for age  
• AST (SGOT)/ALT(SGPT) <  3 x institutional upper limit of normal for age 
• Serum albumin ≥ 3g/dL 
• Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum 
creatinine based on age/gender as follows: 
 
 
Serum Creatinine for age/gender 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the 
Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 
106:522, 1985) utilizing child length and stature data published by the 
CDC. 
 
3.2.11 Pregnancy Status 
Female patients of childbearing potential must have a negative serum pregnancy test at the time 
of enrollment.  
3.2.12 Pregnancy Prevention 
Patients of childbearing or child fathering potential must agree to use adequate contraceptive 
methods while being treated on this study and for   97 days after completing therapy. 


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3.2.13 Informed Consent 
Patient and/or guardian have the ability to understand and the willingness to sign a written 
informed consent document according to institutional guidelines. 
 
 
3.3 
Exclusion Criteria 
3.3.1 Patients with any clinical significant unrelated systemic illness (serious infections or 
significant cardiac, pulmonary, hepatic or other organ dysfunction) that is likely to 
interfere with the study procedures or results 
3.3.2 Patients with low grade gliomas and Rb1 negative tumors  
3.3.3 Patients with QTc interval of > 450 msec or those on medications known to prolong QTc 
interval (see Appendix B) 
3.3.4 Prior treatment on a CDK inhibitor (e.g. Flavopiridol) 
3.3.5 Patients who are receiving drugs that are strong inducers or inhibitors of CYP3A4 (see


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Appendix C) 
3.3.6 Patients who are receiving any other investigational therapy 
3.3.7 Patients who require enzyme inducing anti-convulsants to control seizures 
3.3.8 Patients with cataracts on ophthalmologic examination. The ophthalmology report from 
the institution should clearly specify the presence or absence of cataracts per slit lamp 
examination.  
 
3.4 
Treatment at Primary Institution 
All experimental protocol therapy should be dispensed and all on treatment imaging studies 
should be obtained at the primary PBTC institution. Laboratory studies, excluding 
pharmacokinetic and biologic assays, may be performed at a CLIA certified laboratory of the 
investigator’s choice.  
Imaging utilized to determine eligibility may be performed at an outside institution if all required 
imaging sequences are included and the study is deemed of adequate quality by the treating team. 
All required physical examinations, laboratory parameters need to be performed at the primary 
PBTC institution during the dose finding period of the protocol. 
 
3.5 
Criteria to Start Treatment 
3.5.1 Subjects must start therapy within seven (7) working days of enrollment. 
3.5.2 Laboratory values used to assess eligibility must be no older than seven (7) days prior to 
the start of therapy. Laboratory tests used to determine eligibility need not be repeated if 
therapy starts within seven (7) days. If a test that is repeated after enrollment and prior to 
the start of therapy is outside the limits for eligibility, it must be rechecked 48 hours prior 
to the start of therapy. If the recheck is still outside the limits for eligibility, the patient 
may not receive protocol therapy and will be considered off study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 
REGISTRATION and ENROLLMENT PROCEDURES 
4.1 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
   
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval     
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/investigator_registration_packet.htm. 
For 
questions, please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 


NCI Protocol#: PBTC-042 
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4.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients. Assignment of site registration status in the CTSU 
Regulatory Support System (RSS) uses extensive data to make a determination of whether a site 
has fulfilled all regulatory criteria including but not limited to the following: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
Requirements for PBTC-042 Site Registration: 
• 
IRB approval (local IRB documentation, a CTSU IRB Certification Form, Protocol of 
Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, 
or combination is accepted) 
 
Downloading Site Registration Documents:   
Site registration forms may be downloaded directly from the CTSU website.  
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪ Click on the Regulatory  tab, followed by the Home tab  
▪ Scroll down to “printable CTSU Forms” 
▪ Select and download 2 forms: CTSU IRB Transmittal and CTSU IRB Certification 
 
Requirements for PBTC-042 Site Registration: 
• 
CTSU IRB Certification  
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (Optional) 
 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration status 
page of the members’ section of the CTSU website.  (Note: Sites will be notified by the PBTC 
when all required documents are uploaded to the CTSU Regulatory Office.) 
 
▪ Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
▪ Click on the Regulatory tab at the top of your screen 
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 


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Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Enrollment Procedures 
Screening and patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To 
access OPEN, the site user must have an active CTEP-IAM account (check at < 
https://ctepcore.nci.nih.gov/iam>) and a 'Registrar' role on either the LPO or participating 
organization roster. Registrars must hold a minimum of an AP registration type.   
 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database.  OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the 
CTSU members’ side of the website at https://www.ctsu.org. To assign an IVR or NPIVR as the 
treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer in 
OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used on 
the site’s IRB approval.   
 
Patient enrollment for this study will be facilitated using the Slot-Reservation System in 
conjunction with the Registration system in the Oncology Patient Enrollment Network (OPEN).  
Prior to discussing protocol entry with the patient, all site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available to the patient.  Once a slot- 
reservation confirmation is obtained, site staff may then proceed to enroll the patient to this 
study.  
 
Prior to accessing OPEN, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records. 
 
Patients with DIPG, Medulloblastoma, or ATRT 
For patients with DIPG, Medulloblastoma, or ATRT who are not being screened, reservations 
may also be made through the CTSU OPEN Slot Reservation system providing time to assess the 
patient’s eligibility. Once a slot reservation confirmation is obtained, site staff may then proceed 
to enroll the patient on this study. Non screening reservations will be held for a maximum of 10 
days. The patient’s reservation should be canceled as soon as it is determined that the patient is 
not eligible or that the family/patient has decided not to consent to the trial.  
 
Patients with all other CNS tumors 
All patients with recurrent, progressive or refractory CNS Tumors except DIPG, 
medulloblastoma, or ATRT, must be screened prior to enrollment. Patients must sign the 


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screening consent to send the pre-trial tumor tissue to BTRC Tissue Bank at the University of 
California, San Francisco for Rb1 testing (see Section 9.1.1 for requirement) and have their Rb1 
status confirmed prior to enrolling in the PBTC-042 study. Only patients who are Rb1 positive 
will be eligible to enroll. 
4.3.1 Screening  
Pre-enrollment screening will be performed for patients who are consented for screening and 
willing to provide pre-trial tumor material for Rb1 testing. Sites are required to make a 
reservation using the CTSU OPEN Slot Reservation System before they ship the samples to 
UCSF for screening.  Screening is facilitated by having pre-enrollment screening questions 
completed by a site registrar in the Prerequisite screen of OPEN.  The site must complete the 
steps up to ‘Prerequisite’ to obtain the Enrollment tracking number which will be used for 
labeling the slides. OPEN enrollment will not proceed from the Prerequisite screen until the 
UCSF BTRC lab receives the tumor material, analyzes the tissue and captures the Rb1 result into 
the PBTC ProtoLab database.  
 
Completing the Prerequisite screen sends an automatic email to the UCSF BTRC lab and site 
registrar with information on the screening process. Once the Rb1 result is entered in ProtoLab 
by UCSF BTRC lab, an automatic email will be sent to the site registrar and the responsible 
PBTC Protocol Coordinator indicating that enrollment may proceed. Based on the communicated 
Rb1 screening result, the site registrar must return to OPEN and complete the process – either 
completes enrollment of a patient for treatment who passes the screening, or removes the 
reservation of the patient who fails the screening. 
 
Sites will be notified of the results of the Rb1 testing within 2 weeks. All screened patients who 
are eligible for participating in the PBTC-042 study must be enrolled via OPEN within 10 days 
of the site notification of a patient’s Rb1 status.  
 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of the 
CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
5 
TREATMENT PLAN 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7. Appropriate dose modifications are described in Section 6.2.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's tumor. Treatment must be initiated within seven 
(7) days of enrollment. 
 
5.1 
Agent Administration 
PD-0332991 (IBRANCE) is currently available as 75, 100, and 125 mg capsules (No liquid 
formulation is currently available).  PD-0332991 (IBRANCE) will be given oral daily for 21 
days followed by a week rest (one course = 28 days) for 24 months (26 courses). The starting 
dose will be 50 mg/m2/day for stratum I. The starting dose for stratum II will be one dose level 
below the MTD for stratum I (50 mg/m2/day).  
 
Dosing is based on BSA calculated at the beginning of each course of therapy. The dose 
prescribed should be rounded to the nearest deliverable dose based on the BSA adjustment and 
the available capsule sizes. Dosing Tables are available in Appendix D. Patients will be provided 
with a Medication Diary for PD-0332991 (IBRANCE), instructed in its use, and asked to bring 
the diary as well as the remaining capsule bottles with them to each appointment. The Patient 
Diary is available on the PBTC-042 webpage. 
 
PD-0332991 (IBRANCE) should be taken with food.  Patients are encouraged to take their 
dose at approximately the same time each day. Capsules should be swallowed whole (do not 
chew, crush or open them prior to swallowing). Capsules should not be ingested if they are 
broken, cracked, or otherwise not intact. Patients should be advised to drink plenty of water or 
take hydration fluids to avoid dehydration if diarrhea occurs.  Patients who vomit a dose of PD-
0332991 (IBRANCE) can be re-dosed if capsule is intact in the vomitus, and appropriate anti-
emetic therapy should be implemented prior to the next scheduled dose (see Appendix B for 
contraindicated anti-emetic medications).  
5.1.1 Dose-finding Period 
The dose finding period begins with the initial dose of PD-0332991 (IBRANCE) and ends on the 
last day of course 1.  Should there be a delay starting the subsequent course, dose finding will 
complete on the start date of the subsequent course.  
Dose escalations will be based on toxicities observed during the dose finding period. 
 
5.1.2 Dose Escalation Schedule 
The pediatric equivalent of the adult MTD for the once daily administration of PD-0332991 
(IBRANCE) based on a 3-week on/1 week off schedule is approximately 75mg/m2. PD-0332991 
(IBRANCE) dosing will begin at 50 mg/m2.  The PD-0332991 (IBRANCE) dose will be 
increased in subsequent cohorts until the MTD is reached ( 
Table 7) or the highest proposed dose is determined to be safe.  
 
The  
Table 7 below lists the proposed dose levels to be studied along with the BSA restrictions for 
each dose level for both Strata I and II. At the time of submission of version 8.0, a total of 21 
patients had been enrolled in stratum I. No DLTs were observed in 3 patients enrolled in dose 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
level 1 and 6 patients enrolled in dose level 2. At dose level 3, a total of 6 patients were enrolled 
and 2 were inevaluable for toxicity assessment. Two of 4 evaluable patients at this dose level 
experienced DLTs (grade 4 neutropenia); hence the MTD was exceeded at dose level 3. The 
MTD for stratum I was determined as dose level 2 (75 mg/m2/day) and this stratum has been 
closed to accrual.  
 
 The starting dose level for stratum II is one dose level below the stratum I MTD (i.e. 50 
mg/m2/day). If this dose is well tolerated in the initial cohort of patients enrolled on Stratum II, 
the dose will be escalated to 75 mg/m2/day for the next cohort of patients.  No further escalation 
will be allowed in this stratum.   
 
The plot below the table demonstrates that dosing using the available capsule sizes is feasible for 
the proposed dose levels using the BSA restrictions outlined in the table below. It is not however 
possible to include a level below 50mg/m2/day due to the capsule size limitations. No intra-
patient dose escalation will be permitted on the protocol. Only DLTs observed during the dose-
finding period will be used to guide dose escalation. Dose escalation will be governed by the 
Rolling-6 statistical design separately in each of the two strata, as described in section 13.2 of the 
protocol.  
 
Table 7 
 Stratum I and II: PD-0332991 (IBRANCE) Dosing Regimen and 
BSA Restrictions 
Dose Level 
Dose (mg/m2) 
BSA (m2) 
 1* 
50 
≥ 1.20 
   2** 
75 
≥ 0.93 
3 
95 
≥ 0.70 
 
 
* Starting dose for Stratum II  
 
** MTD for stratum I 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
2.5
2.0
1.5
1.0
0.5
110
100
90
80
70
60
50
40
Body Surface Area (m2)
BSA Adjusted Daily Dose (mg/m2)
50
75
95
50mg/m2
75mg/m2
95mg/m2
Dose
BSA Adjusted Daily Dose vs. BSA 
 
 
5.2 
Dose Limiting Toxicity  
Toxicities will be graded according to CTCAE version 4.0 of the NCI Common Terminology 
Criteria for Adverse Events CTCAE version 4.0 is identified and located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
All appropriate treatment areas should have access to a copy of CTCAE version 4.0. 
Management and dose modifications associated with adverse events are outlined in Section 6. 
 
DLT will be defined as any of the events listed in this section that are at least possibly related to 
the investigational agent that occur during the dose-finding period regardless of expectedness. 
Management and dose modifications for toxicities which occur outside of the dose-finding 
period should also follow section 6; however these will not be considered dose limiting for the 
purpose of dose escalation.    
 
Patients who come off therapy for reasons other than toxicity before completing the dose-finding 
period may be replaced for purposes of estimating the MTD, as discussed in section 13.1.   
 
5.2.1 The following are Dose-Limiting Toxicities (DLT’s) 
o A PD-0332991(IBRANCE) related adverse event will be considered dose-limiting if 
it leads to a dose reduction or permanent cessation of treatment during the first 
course of therapy. All dose modifications in all courses are to follow the guidelines 
provided in section 6.2. 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
o Inability to receive the next cycle of PD-0332991(IBRANCE) within two weeks of 
the last dose because of lack of hematologic recovery or persisting non-hematologic 
toxicity.  
5.2.1.1 Non-hematologic dose limiting toxicity is defined as:  
o Any grade 4 non-hematologic toxicity 
o Any grade 3 non-hematologic toxicity with the exception of: 
▪ Grade 3 nausea and vomiting of < 5 days 
▪ Grade 3 diarrhea and/or electrolyte disturbances which have not been maximally 
treated 
▪ Grade 3 AST/ALT elevation that returns to levels meeting eligibility criteria 
within 7 days of study drug interruption and does not recur upon restarting drug.  
o Any Grade 2 non-hematologic toxicity that persists for > 7 days and is considered 
medically significant or sufficiently intolerable by patients requires treatment 
interruption. 
5.2.1.2 Hematologic dose limiting toxicity is defined as: 
o Grade 3 neutropenia with fever and sepsis 
o Any Grade 4 hematologic toxicity with the exception of lymphopenia 
o Grade 3 thrombocytopenia and/or requiring a platelet transfusion on 2 separate days 
within a 7-day period  
 
5.3 
Criteria for starting subsequent courses 
A course may be repeated every 28 days if the patient has at least stable disease and has again 
met laboratory parameters as defined in Section 3.2.10. The labs can be performed within 48 
hours prior to the start of each course. If a patient does not meet these parameters at the end of 
the treatment course (at day 28), then PD-0332991 (IBRANCE) can be held for up to 7 days until 
parameters meet the eligibility criteria. Drug can be held for up to 14 days in patients who 
undergo surgical procedures for reasons other than tumor progression to allow for proper wound 
healing.  
 
5.4 
Concomitant Medications and Supportive Care Guidelines 
5.4.1 Steroids 
Corticosteroids should be used at the lowest dose to control symptoms of edema and mass effect, 
and discontinued, if possible. Use of corticosteroids should be recorded in the Rave database.   
5.4.2 Anticonvulsants 
Only non-enzyme inducing anticonvulsants drugs should be used, if indicated. Use of such 
anticonvulsants should be recorded in the Rave database. 
5.4.3 Growth Factors 
Routine use of growth factors (i.e. G-CSF, GM-CSF, and erythropoietin) is not permitted.  
However, therapeutic use of G-CSF in patients with serious neutropenic conditions, such as 
sepsis, may be used at the investigator’s discretion. Use of such growth factors should be 
recorded in the Rave database. 
5.4.4 Anti-emetics  
The use of anti-emetics will be at the investigator’s discretion (see Appendix B for 
contraindicated medications).  Use of anti-emetics should be recorded in the Rave database. 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
5.4.5 Proton Pump Inhibitors 
The use of proton pump inhibitors (PPI) (e.g. rabeprazole, omeprazole, pantoprazole, 
lansoprazole or esomeprazole) is not permitted due to a significant decreased exposure to PD-
0332991 (IBRANCE) when concurrently given. If a patient is already receiving a PPI, treatment 
should be discontinued and a wash-out period of at least 24 hours should have elapsed before 
beginning therapy with PD-0332991 (IBRANCE). However, alternative antacid therapies may be 
used including H2-receptor antagonists, and locally acting antacids. H2-receptor antagonists 
should be administered with twice daily dosing regimen. PD-0332991 (IBRANCE) should be 
given at least 10 hours after H2-receptor antagonist evening dose and 2 hours before the H2-
receptor antagonist morning dose. Local antacid should be given at least 2 hours before or after 
PD-0332991 (IBRANCE) administration.  
5.4.6 Febrile neutropenia 
Febrile neutropenia should be managed according to the local institutional guidelines.  Measures 
include laboratory testing, blood and urine cultures, and institution of broad spectrum antibiotics. 
5.4.7 Pneumocystis jiroveci pneumonia (PJP) prophylaxis 
The use of medication (i.e., Bactrim) for PJP prophylaxis in patients on chronic steroids is 
recommended, but is at the investigator’s discretion. 
5.4.8 Neurosurgical Procedures 
If a neurosurgical procedure is required for a reason other than tumor progression (i.e. the onset 
of hydrocephalus), these procedures should be documented, but will not constitute criteria for 
declaring the patient “off therapy”. Due to the possible effect of myelosuppression on wound 
healing, PD-0332991 (IBRANCE) should be held for  at least 7 days or until the patient has  
clinically recovered from the effects of surgery and has demonstrable wound healing before 
resuming treatment. Treatment can be held for up to 14 days.  
5.4.9 Concomitant Therapy 
Other anti-cancer or experimental agents are not permitted. Drugs that are known to interact with 
the investigational agent are not allowed during the trial and are listed in Appendix B, 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Appendix C and Section 8.1.1.11.   
 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s) or disease progression, treatment may 
continue for 26 courses (approximately two years) or until one of the Off Treatment Criteria 
applies as noted in 5.5.2. 
 
5.5.1 On Study Data Submission Schedule 
Pre-treatment, on-study and off-treatment data, as well as patient response data are to be 
recorded in the electronic data collection screens using the Rave database.  See the Required 
Data and Timetable for Submission form located on the PBTC-042 Protocol webpage for the 
schedule.  For assistance, contact the PBTC Protocol Coordinator listed on the cover page. An 
optional roadmap is located on the PBTC-042 Protocol Webpage.  
 
5.5.2 Off Treatment Criteria 
At the discontinuation of treatment, the “Off Treatment Date” is to be recorded in the eCRF and 
is to be consistent with the reason given for going off treatment. The “Last Treatment Date” is 
defined as the last date that the patient received protocol based therapy.  Date of “off treatment” 
must be the greatest of the date of last treatment, date of procedure, date of patient assessment, 
notification of patient/family decision, or decision made by the physician that resulted in the 
patient being taken off protocol treatment.  The reason for discontinuation of treatment must be 
documented by the attending investigator in the medical record and recorded in the eCRF.  
 
Patients will be considered Off Treatment for the following reasons: 
▪ Development of unacceptable toxicity as outlined in section 5.2.1. See section 7 for 
specific reporting requirements. 
▪ Progressive disease (PD) as described in section 11.1.4.   
▪ Development of a medical or psychiatric illness that in the investigator's judgment 
renders the patient incapable of further therapy on this protocol or the treating physician 
determines continuation on this study is not in the patient’s best interest. 
▪ Interruption greater than 14 days of continued drug administration for reasons unrelated 
to toxicity 
▪ The patient, parent or legal guardian refuses further treatment on this protocol. 
▪ Completion of all protocol defined treatment 
▪ Pregnancy 
▪ Non Compliance that in the opinion of the investigator does not allow for ongoing 
participation. 
▪ Termination of the study by the sponsor 
▪ Investigational Agent/Device manufacturer can no longer provide the study agent. 
 
Patients who are off protocol therapy must be followed until an Off Study Criterion is met. 
5.5.3 Data Submission Schedule for Patients Off Treatment    
Subjects will be monitored for the resolution (or return to baseline) of all toxicities considered at 
least possible related to PD-0332991 (IBRANCE) occurring while on treatment and/or within30 
days after the last administration of study drug. Toxicities that are ongoing at the end of day 30 
of last treatment date will be followed until resolution or return to baseline or until the patient is 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
off study.  
 
5.5.4  Criteria for Removal from Study (Off Study Criteria) 
The date and reason for the patient coming off study must be documented in the eCRF and the 
Operations, Biostatistics and Data Management Core must be notified according to standard 
reporting guidelines (see sections 7, 12).  
• Patient determined to be ineligible. 
• Parent, patient, or guardian withdraws consent for continued participation. 
• Patient death while on study. The IRB, Investigational Drug Branch (IDB), Study Chair 
and OBDMC must be notified as per section 7. 
• Initiation of another anti-cancer therapy 
• Patient has been observed for the resolution of all toxicities occurring while on treatment 
and for 30 days following the last administration of study drug.   
o If the patient was found to be ineligible after starting treatment, the 30 day follow-
up would still be necessary unless the patient commences a different anti-cancer 
therapy. 
5.5.5 Data Submission for Patients Off-Study 
No data will be collected documenting treatment or reporting events or disease status that occur 
subsequent to the official “off study” date with the exception of adverse events with an 
attribution of possible, probable, or definite that occur after the “off study” date for the study 
drug.  (see section 7).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6 
DOSING DELAYS/ DOSE MODIFICATION 
6.1 
 Notification of Study Chair 
The study chair or co-chair must be notified of any dosage modifications, prior to the 
implementation of the dose modification 
 
6.2 
Hematologic and Non-Hematologic Adverse Events and Management 
 
 Table 8 
Event 
AE Grade or 
Observation 
Dose Modification 
Diarrhea 
or 
other 
non-
hematologic toxicity 
 
Grade 1 or 2 
Maintain dose; continue anti-diarrheal treatment.  
Grade 
3 
(non-dose 
limiting) 
 
Hold PD-0332991 (IBRANCE) and maximally 
treat. If toxicity resolves to meet on study 
parameters within 14 days of drug discontinuation 
or (as outlined in Section 5.2.1.1), restart treatment 
at the same dose.   
Grade 3 or 4 (dose 
limiting) 
Hold PD-0332991 (IBRANCE) and maximally 
treat. If toxicity resolves to meet on study 
parameters with 14 days of drug discontinuation,  
restart treatment at next lower dose level  if patient 
at dose level 2 or 3 and meets BSA requirements 
for the next lower dose level. If patient at dose 
level 1 or with BSAs smaller than what is required 
should come off treatment permanently. 
If toxicity does not resolve to meet study eligibility 
parameters within 14 days of drug discontinuation, 
the patient must be removed from protocol 
therapy.  
If dose limiting toxicity recurs in a patient who has 
resumed treatment at the reduced dose level, the 
patient must be removed from protocol therapy. 
Hematologic  
 
Grade 1 or 2 
Maintain dose. 
 
Grade 
3 
(non-dose 
limiting) 
Maintain dose. 
Grade 3 or 4 (dose 
limiting) 
Hold PD-0332991 (IBRANCE). Counts should be 
checked at least twice weekly (3-4 days apart) 
during this time. If toxicity resolves to meet on 
study 
parameters 
with 
14 
days 
of 
drug 
discontinuation, restart treatment at next lower 
dose level, if patient is at dose level 2 or 3 and 
meets BSA requirements for the next lower dose 
level. If patient at dose level 1 or with BSAs 
smaller than what is required should come off 
treatment permanently.  
If toxicity does not resolve to meet study eligibility 
parameters within 14 days of drug discontinuation, 
the patient must be removed from protocol 
therapy.  
If dose limiting toxicity recurs in a patient who has 
resumed treatment at the reduced dose level, the 
patient must be removed from protocol therapy.  
 


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7 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Sections 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting".  
 
• Baseline Abnormalities 
Any baseline (pretreatment) abnormalities observed during the initial physical examination 
should be recorded in the Rave database. 
 
• Treatment or within 30 days of treatment 
Only record Grades 1 and 2 adverse events if the attribution is at least possibly related to PD-
0332991.  Record all adverse events Grades 3 through 4 and deaths), regardless of attribution on 
the electronic case report forms. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
7.1 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Palbociclib (PD-0332991, NSC 772256) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 1751 patients. Below is the CAEPR for Palbociclib (PD-0332991). 
 
Version 2.3, January 25, 20181 
 
 Adverse Events with Possible  
 Relationship to Palbociclib (PD-0332991) 
 (CTCAE 5.0 Term) 
[n= 1751] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
 
 
 
 
Febrile neutropenia 
EYE DISORDERS 
 
Blurred vision 
 
 
Dry eye 
 
 
Watering eyes 
 
GASTROINTESTINAL DISORDERS 
 
Constipation 
 
 
Diarrhea 
 
 
Mucositis oral 
 
Nausea 
 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
 
 
 
Fever 
 
INFECTIONS AND INFESTATIONS 
Infection2 
 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 
 
Aspartate aminotransferase 
increased 
 
 
Lymphocyte count decreased 
 
Neutrophil count decreased 
 
 
 
Platelet count decreased 
 
White blood cell decreased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
NERVOUS SYSTEM DISORDERS 
 
Dysgeusia 
 
 
Headache3 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
 Adverse Events with Possible  
 Relationship to Palbociclib (PD-0332991) 
 (CTCAE 5.0 Term) 
[n= 1751] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Epistaxis 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Dry skin 
 
 
Skin and subcutaneous tissue 
disorders - Other (rash)4 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included 
in the e-mail. 
 
2Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
3Headache has been observed in trials using Palbociclib (PD-0332991) in combination with fulvestrant. 
 
4Rash includes rash, rash maculo-papular, erythema, erythematous rash, erysipelas, rash pruritic, rash papular, 
generalized rash, exanthema, allergic dermatitis, dermatitis acneiform, and dermatitis. 
 
5Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy under the 
NERVOUS SYSTEM DISORDERS SOC. 
 
 
Adverse events reported on palbociclib (PD-0332991) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that palbociclib (PD-0332991) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and lymphatic system 
disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Cardiac disorders - Other (paroxysmal atrial 
fibrillation with rapid ventricular response); Palpitations; Pericarditis; Sinus bradycardia; Supraventricular 
tachycardia 
EYE DISORDERS - Cataract; Eye disorders - Other (retinal hemorrhage) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Ascites; Colitis; Colonic 
perforation; Dry mouth; Dyspepsia; Dysphagia; Esophageal stenosis; Flatulence; Gastric hemorrhage; 
Gastrointestinal disorders - Other (gastrointestinal hemorrhage); Intra-abdominal hemorrhage; Lower 
gastrointestinal hemorrhage; Small intestinal obstruction; Small intestinal perforation; Upper gastrointestinal 
hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema limbs; 
Localized edema; Malaise; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (bile duct obstruction); 
Hepatobiliary disorders - Other (jaundice) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Creatinine 
increased; Ejection fraction decreased; GGT increased; INR increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Flank pain; 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Generalized muscle weakness; Muscle cramp; Musculoskeletal and connective tissue disorder - Other 
(osteomyelitis); Myalgia; Neck pain; Osteonecrosis; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL. CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysesthesia; Dysphasia; Intracranial hemorrhage; Nervous 
system disorders - Other (peripheral neuropathy)5; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Psychiatric disorders - Other (altered mental status) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Hypoxia; 
Oropharyngeal pain; Pleural effusion; Pneumonitis; Postnasal drip; Pulmonary edema; Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Pruritus 
VASCULAR DISORDERS - Hypertension; Hypotension 
 
 
Note: Palbociclib (PD-0332991) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
7.2 
Adverse Event Characteristics 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for AE reporting in the RAVE database.  The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized until March 31, 2018 for 
expedited AE reporting.  CTCAE version 5.0 will be utilized for expedited AE 
reporting beginning April 1, 2018. All appropriate treatment areas should have access 
to a copy of the CTCAE versions 4.0 and 5.0.  A copy of the CTCAE versions 4.0 and 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Expedited Adverse Event Reporting  
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The reporting procedures to 
be followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly outlined in the 
tables below (Section 7.3.2). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made by 
telephone 
 to the PBTC Operations Office for instances when the Internet fails. 
Once Internet connectivity is restored, the 24-hour notification phoned in must be entered 
electronically into CTEP-AERS by the original submitter at the site. 


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Version Date: 28 June 2018 
7.3.1 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals: Study Coordinator of the Lead Organization, Principal Investigator, and the local 
treating physician. CTEP-AERS provides a copy feature for other e-mail recipients.  For this 
protocol the following groups should be notified: 
 
The following must be copied on expedited reports (24-hour notification and the complete report) 
submitted via CTEP-AERS: 
 
Study Chair & IND holder: 
David Van Mater, MD, PhD 
 
 
 
 
 
 
 
  
 
 
 
PBTC OBDMC: 
Emily Carps, MBA, CCRA 
  
 
 
 
 
 
 
 
 
 
The site principal investigator should report SAEs as soon as they are determined to meet the 
definition, even if complete information is not yet available. The institution will assist Pfizer in 
investigating any SAE and will provide any follow-up information requested by Pfizer.  
The IND holder will fax the SAE / CTEP-AERS report, within 24 hours of their awareness of the 
event to Pfizer. (Fax 1-866-997-8322). The Reportable Event Fax Cover Sheet provided by 
Pfizer must also be included with each SAE submitted. 
 
The IND holder, Duke University Medical Center shall notify the FDA of any event that is both 
a serious suspected adverse reaction and unexpected in accordance with FDA rules and 
regulations (21 CFR 312.32). Follow-up information to a safety report must also be submitted, as 
requested. 
• If a suspected adverse reaction is determined by the Sponsor to be unexpected and is 
either fatal or considered life threatening, the FDA must be notified as soon as possible 
but no later than 7 calendar days after the initial report was received by the sponsor.  A 
further 8 days is allowed for any additional information to be sent. 
• Serious, suspected adverse reactions that are both unexpected and associated with the use 
of the investigational product, but are not fatal or life-threatening, will be reported to the 
FDA no later than 15 calendar days after the initial report was received by the Sponsor. 
• All other serious adverse events will be reported at the time of submission of the annual 
report. 
 
The PBTC OBDMC will post all IND Safety Letters on the PBTC-042 webpage. Sites will be 
notified via email of the receipt of the IND Safety Letter(s) and instructed to submit these to their 
local IRB in accordance with the institution’s requirements. 
 
A copy of the Annual Progress Reports is submitted by the IND holder as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
regulators by the sponsor-investigator. This submission will be cross-referenced according to 
local regulations to the Pfizer product number at the time of submission. Additionally, a copy of 
these reports will be submitted to Pfizer 
 
 at the time of submission to the appropriate regulatory 
agency. 
7.3.2 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on treatment requires both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 


NCI Protocol#: PBTC-042 
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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in protocol section 
7.3.3. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via  CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.3 Expedited Reporting Exceptions 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP-
AERS.  However, they still must be reported through the routine reporting mechanism (Section 
7.4): 
 
 
7.4 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine (CTMS or CDUS) study data submissions.  AEs 
reported through CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy such as acute myelocytic leukemia 
(AML) 
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
CTCAE 
SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
Blood/Bone 
Marrow 
Lymphopenia 
≤4 
 regardless 
Any 
Expedited reporting is 
not required. 


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Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.6 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8 
AGENT INFORMATION 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
8.1 
PD-0332991 (palbociclib; IBRANCE®) 
8.1.1 Agent Information 
8.1.1.1 Chemical Name:  
6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl) pyridin-2-yl) amino)pyrido[2,3-
d]pyrimidin-7(8H)-one 
8.1.1.2 Other Name: palbociclib, IBRANCE®  
8.1.1.3 Classification: A Cyclin-Dependent Kinases Inhibitor 
8.1.1.4 CAS Registry Number: 571190-30-2 
8.1.1.5 Molecular Formula: 
Freebase (PD 0332991-00) 
 
- C24H29N7O2 
8.1.1.6 Molecular Weight: 
Freebase (PD 0332991-00) 
 
- 447.54 Daltons 
8.1.1.7 Mechanism of Action:  
Oral PD-0332991 (IBRANCE) is a highly selective, reversible inhibitor of cyclin-dependent 
kinases 4 and 6. Inhibition of CDK 4/6 blocks DNA synthesis by prohibiting progression of the 
cell cycle from G1 to S phase.  
8.1.1.8 Formulation:  
PD-0332991 (IBRANCE) is an immediate release capsule. PD-0332991 (IBRANCE) is currently 
available as 75, 100, and 125 mg hard gelatin capsules (No liquid formulation is currently 
available). Dispense in the original container--do not repackage capsules. 
8.1.1.9 Availability and Storage:   
 The study drug should be stored in a safe and securely locked area. Store at 20°C to 25°C (68°F 
to 77°F); brief excursions are permitted between 15° – 30° C (59°F to 86°F). It will be shipped to 
Investigator sites upon request.  
8.1.1.10 Stability:  
Stability is about 18 months and will increase with time as stability studies continue to accrue 
data.  
8.1.1.11 Route of Administration:    
PD-0332991 (IBRANCE) is an oral capsule. PD-0332991 (IBRANCE) should be taken with 
food.  Capsules should be swallowed whole. Do not chew; crush or open capsules prior to 
swallowing. Do not take any capsule that is broken, cracked or otherwise not intact.  
 
Potential Drug Interactions:   
PD-0332991 is metabolized in vitro primarily via CYP3A4. Concomitant administration of 
agents known to inhibit CYP3A isoenzymes (e.g, ketoconazole, miconazole, itraconazole, 
posaconazole, clarithromycin, erythromycin, tilithromycin, nefazodone, diltiazem, verapamil, 
indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and 
grapefruit juice) may increase PD-0332991 exposure and thus are not recommended. 
Concomitant administration of agents that are strong CYP3A inducers (such as phenobarbital, 
rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, and St. John’s Wort) may 
reduce the exposure of PD-0332991 and thus are also not recommended. Proton pump inhibitors 
(e.g., rabeprazole, omeprazole, pantoprazole, lansoprazole, or esomeprazole) have also been 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
shown to produce a significant decrease in PD-0332991 exposure and should be avoided. Based 
on in vitro studies (human liver microsomes and human hepatocytes), PD-0332991 has a low 
potential to produce drug interactions through inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 
2C19, 2D6, (IC50 values all >30 μM) and by inducing CYP3A4 and CYP1A2 activity. In vitro, 
PD-0332991 demonstrated time-dependent inhibition of CYP3A in human liver microsomes. 
 
In vivo, inactivation of this enzyme by PD-0332991 may result in drug interactions with 
compounds that are predominantly metabolized by CYP3A. Therefore, caution must be 
exercised in patients receiving PD-0332991 in combination with drugs that are predominantly 
metabolized by CYP3A. In particular, co-administration of PD-0332991 with CYP3A4 
substrates with narrow therapeutic indices (e.g., astemizole, terfenadine, cisapride, pimozide, 
quinidine, tacrolimus, cyclosporine, sirolimus, alfentanil and fentanyl, excluding transdermal 
patch) or ergot alkaloids (ergotamine, dihydroergotamine) must be avoided. Similarly, PPIs 
(including rabeprazole, omeprazole, pantoprazole, lansoprazole or esomeprazole) should be 
avoided.  
 
The potential for PD-0332991 to inhibit the efflux transporter P-glycoprotein (P-gp, also known 
as multidrug resistance protein 1 [MDR1 and ABCB1]) was investigated in vitro in a Madin-
Darby Canine Kidney (MDCK) II-MDR1 cell line using the known P-gp substrate digoxin.  In 
addition, the potential for PD-0332991 to inhibit the breast cancer resistance protein (BCRP) was 
evaluated using the probe substrate, prazosin, in MDCKII-BCRP cells.  PD-0332991 was a weak 
inhibitor of both P-gp and BCRP, with an IC50 value of >32 µM. The potential of palbociclib to 
inhibit P-gp or BCRP in the GI tract was assessed according to the draft FDA guidance (2012) 
and the EMA guideline (2012).  When the intestinal concentration was calculated to be dose/250 
mL, the values obtained from assessments exceeded the regulatory threshold of a potential drug -
drug interaction (DDI).  However, given the solubility of PD-0332991 is 0.019 mg/mL at neutral 
pH, which is far below 0.5 mg/mL (125 mg/250 mL), the risk for GI interactions with P-gp and 
BCRP is considered to be low at the clinically relevant doses.  At clinically relevant 
concentrations, no drug interaction was observed with hepatic uptake/efflux (organic anion 
transporting polypeptide [(OATP) 1B1 and 1B3] and renal transporters [organic anion 
transporters (OAT1 and 3) and organic cation transporter (OCT-2)]. 
 
8.1.2 Agent Supply and Distribution  
Pfizer will supply IBRANCE for PBTC-042 study as Pfizer will not be replenishing the pool of 
PD-0332991. The description of IBRANCE capsule is identical to the capsule of PD-0332991 
except for the presence of Pfizer logo on the IBRANCE capsule. Each bottle of IBRANCE 
contains 21 capsules.  
 
IBRANCE is supplied in the following strengths and package configurations: 
 
IBRANCE Capsules 
Package 
Configuration  
Capsule 
Strength (mg)  
NDC  
Capsule Description  
Bottles of 21 
capsules  
125  
NDC 0069-0189-21  
opaque, hard gelatin capsules, size 0, with 
caramel cap and body, printed with white 
ink “Pfizer” on the cap, “PBC 125” on the 
body  


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Bottles of 21 
capsules  
100  
NDC 0069-0188-21  
opaque, hard gelatin capsules, size 1, with 
caramel cap and light orange body, 
printed with white ink “Pfizer” on the 
cap, “PBC 100” on the body  
Bottles of 21 
capsules  
75  
NDC 0069-0187-21  
opaque, hard gelatin capsules, size 2, with 
light orange cap and body, printed with 
white ink “Pfizer” on the cap, “PBC 75” 
on the body  
 
8.1.3 Agent Ordering and Agent Accountability 
PD-0332991 (IBRANCE) may be requested by the Principal Investigator or designees at each 
participating institution. All regulatory documents, as required by the PBTC, must be current and 
up to date prior to requesting the study drugs. Drug request form can be found on the PBTC-042 
protocol and resources webpage. The form can be emailed or faxed to Pfizer.   
 
The investigator, or a responsible party designated by the investigator, must maintain accurate 
records regarding study drug receipt, dispensing, use and disposal using the NCI Drug 
Accountability Record Form (DARF).  See the CTEP home page at http://ctep.cancer.gov or the 
NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage. 
 
Any unused/used/expired study drug and containers may be destroyed according to the 
institutional standard operating procedure. The method and the record of destruction must be 
documented and maintained at the site.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
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9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
This section contains the collection, shipping and handling information for all planned biomarker 
and exploratory correlative studies, neuropathology review and research imaging.  The table 
below identifies the tests, sample type and amount, analyzing laboratory and whether it is 
required or optional.  For additional details, please review the associated section below. 
 
Test Name 
 
Sample Type and Amount 
Analyzing 
Laboratory 
Required or 
Optional 
Section 
ID 
Assessment for 
tumor Rb1 protein 
FFPE tumor tissue – 2 unstained slides 
+ 1 H&E stained slide 
UCSF BTRC  
Required 
9.1.1 
Laboratory Correlative Studies 
Pharmacogenetic  
Whole blood – 5  mL 
Stewart Laboratory 
Optional 
9.2.1 
Pharmacokinetics 
Plasma – 2 mL per sample 
Stewart Laboratory 
Required 
9.2.2 
Pharmacokinetics 
after 
discontinuation of 
dexamethasone 
Plasma – 2 mL per sample 
Stewart Laboratory 
Optional 
9.2.2 
Assessment of 
Cyclin D1,Cyclin 
D2, Cyclin D3, 
CDK4, CDK6 and 
Ink4a-ARF loss  
FFPE tumor tissue 
10 unstained slides or tissue block 
Will Parsons, MD 
Texas Children’s 
Hospital 
Optional 
9.3.3 
Central 
Neuropathology 
Review 
1 H&E stained slide 
PBTC CRB at 
CHLA 
Optional 
9.3.2 
PBTC CRB 
Repository Samples 
20 unstained slides and blood for 
future research  
PBTC CRB at 
CHLA 
Optional  
9.3.1 
 
9.1 
Integral Biomarker Studies 
9.1.1 Assessment for Tumor Retinoblastoma (Rb1) protein  
Formalin fixed paraffin embedded tumor tissue will be collected from all patients prior to 
enrollment (except for those with diffuse intrinsic pontine gliomas, medulloblastoma, or ATRT 
who do not require testing).  Unstained slides and a corresponding H&E stained slide will be sent 
to UCSF BTRC for Rb1 immunohistochemistry and interpretation. The turn-around time for this 
test is approximately 2 weeks. Tumor Rb1 protein status will be denoted as “positive” if ≥20% of 
tumor cells have positive nuclear staining. Rb1-positive endothelial cells will serve as an internal 
positive control. All slides will be centrally reviewed by the Neuro-pathologist, Joanna J. 
Phillips, MD.  
 
9.1.1.1 Assay Method 
Immunohistochemistry for Rb1 will be performed as previously described30 using a mouse 
monoclonal anti-Rb1 antibody (G3-245; BD Biosciences, San Jose, CA) and an automated IHC 
staining process (Benchmark XT; Ventana Medical Systems, Inc, Tucson, AZ).  Briefly, antigen 
retrieval will be performed in Tris, pH8.0 at 95C for 1 hour, followed by incubation in 3% H2O2 
for 16 min, and primary antibody at 1:100 at room temperature for 60 minutes.  
Immunohistochemistry will be scored as follows:  0, denotes expression in less than 20% of 
tumor cells; 1, denotes expression in 20% to 50% of tumor cells; and 2, indicates positive 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
expression in more than 50% of tumor cells. At least three 20x-fields will be evaluated per case.  
The assay is performed and interpreted in a laboratory that is CLIA certified to perform high 
complexity testing. The immunohistochemistry assay for Rb1 is not FDA approved.  
 
9.1.1.2 Collection and shipping of Specimen(s) 
Two unstained slides from formalin-fixed paraffin-embedded tumor material will be collected 
along with one H&E stained slide prepared from the same block. 
Slides must be shipped from the site to UCSF BTRC within 2 business days of reservation. 
Slides must be labeled with the PBTC Enrollment tracking number, patient’s date of birth, 
protocol number, and date of collection. Samples should be shipped Monday through Thursday 
using the PBTC-042 FedEx account. Weekend deliveries are not permitted. The sample 
collection and shipping dates must be documented in the eCRF by the sites.  
 
Send the following to UCSF BTRC Biomarkers Laboratory: 
1-H&E stained slide from best block 
2-Unstained slides from best block 
Completed Specimen Transmittal Form 
 
All specimens should be shipped at room temperature with a completed Specimen Transmittal 
Form (found on the PBTC-042 website) to:  
 
Attn:  Anny Shai, Ph.D. 
 
 
 
 
 
 
 
 
9.2 
Laboratory Correlative Studies 
9.2.1 Pharmacogenetic Studies 
Pharmacogenetic studies will be obtained from consenting patients enrolled on this protocol prior 
to starting treatment.  Prior to the first PD-0332991 (IBRANCE) dose, collect 5 mL of whole 
blood for isolation of peripheral mononuclear cells, which will be used for DNA extraction by 
standard techniques. Samples may be collected after PD-0332991 (IBRANCE) treatment has 
begun with the prior approval of Dr. Clinton Stewart or his designee (901-595-2400). 
Pharmacogenetic samples should be shipped using PBTC-042 PK/PG FedEx account details, as 
per PBTC member website.  
 
9.2.1.1 Sampling Collection and Processing Instructions  
Upon request, each participating institution will receive a Pharmacogenetics (PG) Kit from Dr. 
Clinton Stewart for the collection of samples from consenting patients.  Collect 5 mL of blood in 
a purple-top tube for PG studies before starting PD-0332991 (IBRANCE) treatment.  The 
sample should not be batched and should be shipped as soon as possible, within 48 hours of 


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sample collection, to St. Jude Children’s Research Hospital with the cold ice pack included in 
kit. The blood sample should be kept on ice or at 4°C until shipped.  Shipments should be made 
Monday through Thursday; weekend and holiday deliveries should be avoided.  Please contact 
the Stewart Laboratory 
 to request a Pharmacogenetics Kit. 
 
DNA extraction by standard techniques will be performed
 
 
 
 
 
 
 Genotyping for pharmacogenetic 
polymorphisms will be assessed using standard molecular techniques.  No patient identifiers will 
be available to the laboratory personnel conducting the genotyping analyses, as they will be 
conducted using designated PBTC accession numbers alone. 
 
Patient and institution information should be recorded on the Pharmacogenetics Sample 
Transmittal Form (can be found on the PBTC – 042 ‘Protocol and Resources’ web page as ‘PG 
sample transmittal form’) on the day the sample is collected. The PG Sample Transmittal Form 
should be sent with the sample to the address below to maintain confidentiality of the 
pharmacogenetic specimens. Samples should be shipped using PBTC-042 PK/PG FedEx account 
details, as per PBTC member website within 48 hours of sample collection.  
 
Stewart Laboratory 
 
 
 
 
   
 
 
 
9.2.2 Plasma Pharmacokinetics Studies 
Plasma pharmacokinetic studies will be obtained from all patients enrolled on this study on days 
1, 2, 3, 21 and 22 of Course 1 to evaluate the pharmacokinetics of PD-0332991 (IBRANCE). On 
Day 2 of Course 1, the dose of PD-0332991 (IBRANCE) will be held to obtain 
pharmacokinetic studies. No other doses should be held for pharmacokinetic purposes. Serial 
pharmacokinetic studies will be repeated approximately 2 weeks after discontinuation of 
dexamethasone in patients who were previously receiving this medication. 
 
9.2.2.1 Sampling Strategy 
On Day 1 of Course 1, serial blood samples for PD-0332991 (IBRANCE) pharmacokinetic 
studies will be collected at the following times: pre-dose and at 0.5, 1, 2, 4, 8 (±1), 10 (±0.5) 
[optional], 24 (±4), and 48 (±4) hours after the oral dose. In order to obtain the 24 and 48-hour 
time points, the dose on Day 2 will be held. It is crucial that the 48-hour time point be 
obtained prior to dose administration on Day 3.  
 
On Day 21 of Course 1, serial blood samples for PD-0332991 (IBRANCE) pharmacokinetic 
studies will be collected at the following times: pre-dose and at 1, 2, 4, 8 (±1), 10 (±0.5) 
[optional], and 24 (±4) hours after the dose (prior to the next administered dose).  
 


NCI Protocol#: PBTC-042 
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For children less than 13 kg, contact Dr. Clinton Stewart or his designee 
for a 
sampling strategy with reduced blood requirements. 
 
Pharmacokinetic Studies after Discontinuation of Dexamethasone (if consented) 
Any patient who received dexamethasone during the mandatory PD-0332991 (IBRANCE) 
pharmacokinetic studies should have serial blood samples obtained at least 14 days after 
discontinuation of dexamethasone, and after 14 days of continuous dosing with PD-0332991 
(IBRANCE). At a routine clinic visit samples for pharmacokinetic studies should be obtained at 
the following times: pre-dose and at hours 1, 2, 4, 8 (±1), 10 (±0.5) [optional], and 24 (±4) hours 
after the dose (prior to the next administered dose).    
 
9.2.2.2 Sampling Collection and Processing instructions 
At each time point, 2 mL of blood will be collected into appropriately labeled tubes containing 
K2EDTA. Two mL of blood is needed to provide approximately 1 mL plasma for 
pharmacokinetic analysis. Record the exact time that the sample is drawn along with the exact 
time that the drug is administered on the Pharmacokinetic Data Collection Form that is available 
on the PBTC-042 webpage.   
During the sample collection and processing steps, the blood and plasma should be kept out of 
direct sunlight and unfiltered lab light. Upon collection of the blood PK samples in K2EDTA 
blood collection tubes, keep the blood samples on wet ice at all times prior to processing to 
plasma. Samples will be centrifuged at approximately 1700 x g for about 10 minutes at 4C 
(Note: If a refrigerated centrifuge is not available, please refer to the Shipping Manual located on 
the PBTC-042 webpage for further instructions).  The plasma will be stored in an appropriately 
labeled amber screw-capped polypropylene tube at approximately -20C within 1-hour of 
collection.  
9.2.2.3 Handling of Specimens(s) 
The blood to plasma sample processing requires using refrigerated centrifuges. The samples 
should be stored at -20ºC. The established long-term stability (LTS) of PD-0332991 (IBRANCE) 
in frozen plasma stored at -20 ºC or -70 ºC is 439 days. Additional testing is to be conducted to 
extend the LTS.  
9.2.2.4 Shipping of Specimen(s) 
At the start of the study, each participating institution will receive a Pharmacokinetics (PK) kit 
from Dr. Clinton Stewart for the collection of samples.  
 
Samples should be shipped for delivery Monday through Thursday with a generous amount of 
dry ice enclosed to safeguard against shipping delays. Weekend and holiday deliveries should be 
avoided. Sites should contact the Stewart Laboratory at St. Jude Children’s Research Hospital, at 
 to request a Pharmacokinetics Kit for each patient enrolled on the study. 
 
Samples should be shipped within 30 days of the last sample being taken. The site should use the 
PBTC-042 PK/PG FedEx account details, located on the PBTC member website. Ship all 
pharmacokinetic samples on dry ice along with a completed Pharmacokinetics Sample 
Transmittal Form (located on the PBTC 042 webpage in the “Protocol Specific 
Instructions/forms” section) to: 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Stewart Laboratory 
 
 
 
 
   
 
 
 
Samples must be shipped from the site to the respective laboratory within 30 days of last sample 
collection in order to receive cost reimbursement. The sample collection and shipping dates must 
be documented in the eCRF. 
 
9.2.2.5  Description of PD-0332991 Assay 
PD-0332991 PK is measured in K2EDTA plasma samples. The LC-MS/MS-based method 
identifies both PD-0332991 and its lactam metabolite ((PF-05089326) but will be used for 
measuring PD-0332991 levels only.  The assay is fully validated and meets the criteria for the 
validation method defined in the FDA and EMA Guidance documents and executed in a Pfizer 
approved US-based laboratory (not CLIA certified). 
The method has been successfully used for the analysis of PD-0332991 PK samples from 
multiple Pfizer sponsored studies. The assay dynamic range for PD-0332991 is from 1 to 
250ng/mL.  
 
NOTE: The validated dilution may change depending upon the concentrations of the study 
samples outside the curve and are validated during the sample analysis phase if required more 
than a 10-fold dilution. 
9.2.2.6 Description of Pharmacokinetic analysis 
 
The PD-0332991 plasma concentration-time data will be analyzed with both compartmental and 
non-compartmental approaches. The noncompartmental analysis will provide an estimate of the 
maximum concentration (Cmax), minimum concentration (Cmin), area under the concentration-
time curve, and apparent oral clearance. 
 
Pharmacokinetic data will also be analyzed using nonlinear mixed effects modeling (NONMEM 
v.7). For PD-0332991, an appropriate compartmental pharmacokinetic model will be fit to the 
data. Estimated pharmacokinetic parameters may include the absorption rate constant (ka), 
apparent oral clearance (CL/F), apparent volume of distribution (V1/F), peripheral volume of 
distribution (V2/F), and distributional clearance (Q/F). The typical population value and inter-
individual variability of each parameter will be determined using NONMEM. Demographic and 
clinical chemistry covariates will be examined graphically (via individual Bayesian parameter 
estimates) and by using generalized additive modeling. Potentially significant covariates will be 
tested in the NONMEM population model. 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
9.3 
Pathology and Exploratory Correlative Studies 
The Pathology Central Review and Biorepository (CRB)’s function is to collect, distribute and 
store specimens for central pathology review and planned correlative studies which support the 
laboratory objectives of this protocol.   
 
The CRB will also serve as a central repository for specimens collected for future research and 
left over specimens (tumor tissue, blood, urine or CSF) returned to the repository following the 
planned analysis from patients who consent to long term storage of unused specimen.  These 
samples will be stored in the repository for undefined future studies which support the mission of 
the PBTC.  If the patient does not consent to participation in the repository, correlative 
study samples should be submitted following the guidelines in the appropriate correlative 
study section below (9.3.3). If the patient does not consent to long term storage, remaining 
correlative study samples will be destroyed once the PBTC-042 analysis is complete. 
 
9.3.1 PBTC CRB Submission Guidelines  
If the patient consents to provide slides for submission to the repository at the time of 
participation in a PBTC trial, the following should be submitted:  
• Tumor material 
Slides from the original and/or recurrent surgery should be prepared for storage. The site 
should provide up to twenty (20) unstained sections cut at 4µm in thickness on (+) slides 
from the most representative section. For patients who have consented to other 
correlative studies (e.g. genomics) on this protocol that require slides, these submitted 
slides will be used for the conduct of studies outlined in the corresponding section below 
(9.3.3).  Fewer unstained sections may be submitted based on size and availability of 
tissue.  Preference is for tissue that has not previously been frozen.   The corresponding 
pathology 
report 
(s) 
including 
immunohistochemical, 
special 
stains, 
and 
molecular/genetic results is to be uploaded to the PBTC using the secure File Upload 
system.  These reports will be made available to the pathologist via a link in the 
ProtoLab. 
 
Suitability of sections would be established by preparing one (1) H&E to ensure that the 
sections meet the following criteria:  
o histologically representative of the reported lesion 
o contain at least 60% viable tumor 
o no more than 40% necrosis 
 
• Peripheral Blood Mononuclear Cells and Plasma 
PBMC may be collected by processing a 2-5 mL whole blood specimen with Ficoll or 
collecting the specimen in a BD Vacutainer™ CPT™ Cell Preparation Tube with Sodium 
Citrates as noted below. Once separated, all pellets must be snap frozen and stored at 
least at -20oC prior to dry ice shipment. 
 
Specimen Collection and Processing by Ficoll tube 
• Collect 2 – 5 mL of fresh blood into an EDTA tube. 
• Transfer blood into a sterile 50-mL tube and add double the amount of PBS. MIX 
GENTLY. 


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• Set up another tube containing half of its total volume of Ficoll. For example, if there is 
15 mL of blood + PBS, then use 7.5 mL of Ficoll (2:1 ratio). 
• At very slow pace (approx. 2 mL/minute), layer the blood + PBS mixture onto the Ficoll 
so that the solutions DO NOT MIX. Spin the blood/Ficoll at 750 g in slow mode for 30 
minutes @ 25ºC. After spin you will see four distinct layers: plasma (top layer), white 
fluffy ring (2nd layer), Ficoll (3rd layer), and blood (bottom layer). 
• Remove plasma layer down to about 1 mL above the white fluffy ring and dispense into 
cryovials.  Freeze the cryovials within 1 hour of collection and store immediately at -
20°C or colder. 
• Collect the entire white fluffy ring. If ring is hard to see, also take extra liquid above. 
Then discard everything else. 
• Place this fraction of white blood cells into a fresh 50 mL sterile tube with 20 mL of PBS.  
Spin down for 10 minutes @ 25ºC, 750 g in fast mode. Remove the supernatant. Add 
back to pellet 1 mL of PBS and spin for 5 min. at 4°C at 10000rpm. Remove supernatant.  
• Freeze the pellet of WBCs and store at -80ºC until shipment. 
• Ensure that all tubes are clearly labeled with the PBTC patient accession number. Please 
ensure that the labeling system used is designed to withstand temperatures down to -
80oC. Samples should be stored at -80ºC until shipment. For short term storage (2-3 
weeks) -20ºC is acceptable. NOTE: 4ºC IS NOT ACCEPTABLE STORAGE.  
 
If it is not possible to collect the PBMC by Ficoll gradient then separation of PBMC can be 
conducted using CPT tube separation as an alternative. However the PBMC pellet MUST BE 
frozen immediately and stored at -80oC. 
 
Collection and Processing by CPT tube 
• Peripheral blood should be collected in a BD Vacutainer CPT™ Cell Preparation Tube 
with Sodium Citrate. 8 mL and 4 mL CPT tubes can be obtained from Fisher Scientific 
(Cat# 02-685-125, 02-688-81) or Becton-Dickinson (BD No.362761, 362760).  The 8 mL 
tubes have a 6 mL minimum draw and the 4 mL tubes have a 3 mL minimum draw.  
• Centrifuge the CPT™ tube at 1500 x g for 30 minutes at room temperature (20o C to 25o 
C). DO NOT APPLY THE BREAK ON THE CENTRIFUGE.  Use acceleration 5, brake 
0 (“slow mode”).   
• It may be necessary to spin the tube longer to ensure that all of the red blood cell 
components have been separated from the plasma layer through the polyester gel barrier. 
• The tube should be removed immediately from the centrifuge. The mononuclear layer 
and plasma lie above the polyester gel plug. 
• Using a sterile stripette, remove as much of the plasma component (upper half of the CPT 
tube) without disturbing the mononuclear layer if possible and aliquot it into cryovials.  
Freeze the cryovials within 1 hour of collection and store immediately at -20°C or colder. 
• Transfer mononuclear cell layer (and some residual plasma layer) to a labeled 15-mL 
conical centrifuge tube and add 5 mL sterile room temperature magnesium or calcium-
free phosphate buffered saline (PBS) to fill the conical tube and recap. 
• Centrifuge at 450 x g for 10 minutes at room temperature (20o C to 25o C).  Use 
acceleration 9, brake (“fast mode”).  
• Remove supernatant, being careful not to aspirate the cellular pellet at the bottom of the 
tube.  


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• Add 1mL of sterile PBS to the pellet and gently re-suspend by pipetting up and down. 
Transfer the entire suspended pellet to the labeled cryovial.   
• Centrifuge the cryovial at 450 x g for 5 minutes (or spin down the microcentrifuge tube at 
1300 x g for 5 minutes) at room temperature. Discard the supernatant. 
 
Store the cell pellet cryovial frozen at -80ºC. For short term storage (2-3 weeks) -20o C is 
acceptable. 
 
If the patient consents to other secondary correlative studies as outlined in section 9.3.3, the 
following specimens may also be submitted to the CRB for distribution and storage.   
 
• Formalin-fixed, paraffin-embedded (FFPE) slides or an FFPE tissue: quantity and 
schedule of collection as outlined in section 9.3.3. 
 
9.3.1.1 Handling of Specimens 
• Slides are to be labeled with the study ID and the patient PBTC Accession # and these 
slides should be designated as PBTCR # (where the # assigned from 1 to 20, or the 
highest number of unstained sections prepared, sequentially) or PBTCR H&E for the 
H&E stained section.  
 
• Formalin Fixed, Paraffin Embedded (FFPE) tumor materials are to be labeled with the 
PBTC Accession # and the PBTC study for which the sample is provided.  FFPE tumor 
material should be shipped at room temperature.  
 
• PBMCs are to be labeled with the PBTC Accession # and the PBTC study for which the 
sample is provided.  Samples should be shipped overnight in a separate box with a 2-day 
supply of dry ice unless otherwise specified.  
 
9.3.1.2 Shipment of Specimens 
Samples collected for the repository should be sent to the PBTC CRB overnight via FedEx 
Monday through Thursday by completing the Internet form at http://www.fedex.com/us/ and 
requesting FedEx to e-mail researchsupportbiorepository@chla.usc.edu. FedEx user ID and 
password for pathology shipping can be found at PBTC-042 protocol webpage. Samples should 
be shipped in the appropriate environment as described in Section 9.3.1.1. Samples are to be 
shipped to: 
 
PBTC CRB 
 
 
 
 
 
   
 
 


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9.3.2 Pathology Central Review  
Central pathology review is optional for this study. In consenting patients, samples for central 
pathology review will be completed from the slides submitted to the PBTC CRB.  
 
Pathologist review for this study will include the following elements:  
• Examination of H&E stained slides and, if the tumor being reviewed is residual, recurrent 
or metastatic, examination of H&E slides from the original primary tumor. For each 
subject one (1) H&E stained slide per one representative block from the brain tumor, 
removed either at initial diagnosis or relapse, should be submitted for review. 
• Review of the corresponding pathology report(s) of the immunohistochemical, special 
stains, and molecular/genetic results from current and/or original primary tumor 
• If necessary, review of immunohistochemical or special stained slides. Slides submitted 
to the PBTC CRB will be digitized to 40X. H&E stained sections will be retained and 
filed at the CRB.  Original immunohistochemical or special stain slides will be returned 
to the submitting institution. 
 
9.3.3 Assessment of Cyclin D1, Cyclin D2, Cyclin D3, CDK4, CDK6, and Ink4a-ARF loss  
 
Description of Assay 
Array CGH is a superior approach to detect amplifications and deletions of genes such as cyclin 
D1, cyclin D2, cyclin D3, CDK4, CDK6, and Ink4a-ARF loss. The assay will be array CGH 
using the Agilent 1M microarray. Minimum required genomic DNA from FFPE tissue is 2,000 
ng.  Ten unstained FFPE slides would be required (although it depends on the genomic DNA 
yield per slide). It is of particular interest to look for the following copy number variations: 
Cyclin D1, Cyclin D2, Cyclin D3, CDK4, CDK6, Ink4a-ARF loss, and possibly others. The 
median probe spacing is 2.1-kb which allows for the detection of smaller more focal 
amplifications and deletions.     
9.3.3.1 Collection of Specimen(s) 
 
10 unstained slides from formalin fixed, paraffin wax embedded (FFPE) tumor material will be 
collected at the time of enrollment from all patients who have agreed to participate in this 
correlative study.   
Either 10 unstained 5 um formalin-fixed, paraffin-embedded (FFPE) slides or an FFPE tissue 
block from tumor material will be collected. Use air-dried non-charged, non-coated slides. Oven 
drying of slides should be avoided. Samples must be labeled with the PBTC accession number, 
protocol number and date of collection. Specimens should be shipped at room temperature along 
with a completed Specimen Transmittal Form found on the PBTC-042 website.   
 
9.3.3.2  Handling of Specimens(s) 
FFPE slides or tissue blocks should be stored at room temperature. 
9.3.3.3  Shipping of Specimen(s) 
The slides should be shipped at room temperature to the PBTC CRB Monday through Thursday 
via Federal Express Priority Overnight using the FedEx account information and transmittal 
form, found on the PBTC-042 Protocol and Resources web page. Weekend deliveries are not 
permitted. Receipt and processing of biological materials will be recorded in ProtoLab, as 
appropriate, by staff at the PBTC CRB. The sites sending the materials must document sample 


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collection and shipping dates in the eCRF. Specimens should be sent to the following address:  
 
 
PBTC CRB 
 
 
 
 
 
   
 
 
9.3.3.4 Site(s) Performing Correlative Study   
Will Parsons, MD PhD 
 
 
 
 
 
9.4 
Neuroimaging Studies  
Patients will have MRI brain with and without contrast performed prior to initiation of therapy, 
after courses 2, 4, 6, then every 12 weeks and at the time of end of treatment. MRI Spine should 
be performed prior to therapy and at the same time points as standard MRI brain, if clinically 
indicated.  
9.4.1 Image Transfer 
Only scans showing a response, the confirmation scan obtained approximately 8 weeks later if 
available and the corresponding baseline scan will be electronically transferred to the PBTC 
Neuroimaging Center (NIC) for central review.  
 
All patient specific data are stripped from the images and replaced with PBTC Subject Accession 
number prior to transmitting the images to the NIC. All image data transfer is accomplished 
using pretty-good-privacy (PGP) 128-bit encryption, which meets industry standard for secure 
communication. 
 
9.4.2 Discipline Review: Neuro-imaging  
Local review of MR imaging studies at each site and central review of the MR imaging studies 
will be conducted through the PBTC Neuroimaging Center (NIC). The director and one 
Neuroradiologist of NIC will review the imaging studies at study completion. If the local and 
central review are not in agreement the NIC neuroradiologist will confer with the participating 
site to determine why there is a discrepancy via conference call. 
 
NIC review will include assessment of response to therapy (as feasible). All patients with a 
documented PR/CR at any time point will have central review of the scan showing response, the 
confirmation scan obtained approximately 8 weeks later, as well as the corresponding baseline 
scan conducted for confirmation. 


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10 STUDY CALENDAR  
 
 
Pre-
therapy 
Course 1 
Course 2- 
Course 26 
Completion/ 
Discontinuation 
 Of Treatment 
PHYSICAL ASSESSMENTS 
 
 
 
 
Medical history  
X 
  Weekly 
 X 
X 
Physical exam /height/weight 
X 
  Weekly 
 X 
X 
Vital signs 
X 
  Weekly 
 X 
X 
Performance status 
X 
  Weekly 
 X 
X 
Neurologic exam  
X 
  Weekly 
 X 
X 
LABORATORY EVALUATIONS 
 
 
 
 
CBC - WBC, HgB, Hct, Platelets, ANC, 
ALC  
X 
  WeeklyA 
WeeklyA, B 
X 
Serum Chemistry - Sodium, Potassium, 
Bicarbonate, Chloride, Calcium, BUN, 
Creatinine, Glucose, Phosphorous, 
Magnesium, Albumin, Total Protein 
X 
 Weekly 
 XB 
X 
SGPT (ALT), SGOT (AST), Alkaline 
phosphatase, Total Bilirubin 
X 
 Weekly 
 XB 
X 
Serum pregnancy test (for females of 
childbearing potential)  
X 
XB 
XB 
 
CSF cytology (if clinically indicated) 
X 
 
 
 
OTHER ASSESSMENT 
 
 
 
 
12-lead EKG  
X 
XC 
XC 
XC 
Ophthalmology Examination (including slit 
lamp) 
X 
 
XD 
 
IMAGING ASSESSMENTS 
 
 
 
 
Brain MRI (standard)  
X 
 
XE 
X 
Spine MRI (if clinically indicated) 
X 
 
XF 
X 
CORRELATIVE STUDIES 
 
 
 
 
Screening Pre-trial tumor materials for Rb1 
testing (required for patients with all types 
of CNS tumors except DIPG, 
medulloblastoma, ATRT) 
XG 
 
 
 
Pharmacogenetic Studies (if consented) 
XH 
 
 
 
Plasma Pharmacokinetic Studies (required) 
XI 
XI 
 
 
Plasma PK after discontinuation of 
dexamethasone (if consented) 
 
Any time after stopping  
dexamethasone I 
 
Pre-trial tumor materials for Genomics (if 
consented) 
XJ 
 
 
 
Tumor Tissue and blood for Biorepository 
(if consented) 
XK 
 
 
 


NCI Protocol#: PBTC-042 
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Pre-
therapy 
Course 1 
Course 2- 
Course 26 
Completion/ 
Discontinuation 
 Of Treatment 
A. CBC with differential at baseline and q weekly during each cycle for the first 3 cycles; consideration can be given 
to increase interval to q 2 weeks from course 4 onwards if the patient has no DLT in the previous cycle. If patient 
develops Grade 4 neutropenia or thrombocytopenia, then CBCs should be checked every 3-4 days until recovery to 
Grade 3.        
B. Within 48 hours of beginning protocol therapy and each course (see 5.3). 
C. 12-lead EKG at baseline, and 3 hours post dose on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 and 3. 
Thereafter, EKG should be done prior to the start of every 3rd cycle (prior to 6, 9, 12, 15, 18, 21, 24 and end of 
treatment).  
D. Eye exam is to be done at baseline, and every 3 months (after courses 3, 6, 9, 12, 15, 18, 21, 24). The 
ophthalmology exam report should clearly specify the presence or absence of cataracts and data must be recorded 
in Rave database. 
E. Standard imaging is to be done every 8 weeks (after courses 2, 4, 6) and then every 12 weeks thereafter through the 
26 courses and at the completion of treatment.   
F. MRI Spine should be done at the same time points as the standard MRI brain, if clinically indicated. 
G.  2 unstained slides from FFPE block and 1 H&E slide required to be submitted for Rb testing (see 9.1.1) 
H. Obtain 5 mL of whole blood prior to 1st dose if consented (See section 9.2.1 for details) 
I. 
Plasma PK (required) – D1 Course 1: pre-dose, 0.5, 1, 2, 4, 8, 10, 24, 48 hrs after dose  
D21 Course 1: pre-dose, 1, 2, 4, 8, 10, 24 after dose  (See section 9.2.2 for details of  Plasma PK)  
Plasma PK after discontinuation of dexamethasone (if consented) – see section 9.2.2 
J. 
10 unstained slides from FFPE block or FFPE tissue block [See section 9.3.3  for details of  Pre-trial tumor 
materials for Genomics (if consented)] 
K. Biorepository samples (if consented) – 20 unstained FFPE slides and blood. Obtain 2-5 mL of whole blood at 
baseline. If unable to collect at baseline, it can be collected any time during protocol therapy. See section 9.3.1 for 
details.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11 MEASUREMENT OF EFFECT 
11.1 Tumor Response Criteria  
11.1.1 Complete Response (CR) 
 Complete disappearance on MR of all enhancing tumor and mass effect, on a stable or 
decreasing dose of corticosteroids (or receiving only adrenal replacement doses), accompanied 
by a stable or improving neurologic examination, and maintained for at least 8 weeks.  If CSF 
was positive for malignant cells, it must be negative.  
11.1.2 Partial Response (PR) 
Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as 
compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, 
accompanied by a stable or improving neurologic examination, and maintained for at least  8 
weeks. If CSF was positive for malignant cells, it must be negative.  
11.1.3 Stable Disease (SD) 
Neurologic exam is at least stable and maintenance corticosteroid dose not increased, and 
MR/CT imaging meets neither the criteria for PR nor PD.  CSF can be positive or negative for 
malignant cells. If this category is to be reported as of possible clinical benefit, Stable Disease 
status must be maintained for at least 4 courses.   
11.1.4 Progressive Disease (PD) 
Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status 
not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid 
toxicity, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR a greater than 25% increase in 
the bi-dimensional measurement, taking as a reference the smallest disease measurement 
recorded since the start of protocol therapy, OR the appearance of a new lesion (including new 
appearance of malignant cells in the CSF), OR increasing doses of corticosteroids required to 
maintain stable neurological status or imaging. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12 DATA REPORTING/ REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.  
12.1 Data Reporting 
12.1.1 Responsibility for Data Submission  
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS).  To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam>) and the appropriate Rave role (Rave CRA, Read-Only, CRA 
(Lab Admin, SLA or Site Investigator) on either the LPO or participating organization roster at 
the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type.  To hold the Rave Site Investigator role, the individual must 
be registered as an NPIVR or IVR.  Associates can hold read-only roles in Rave.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com.   
 
Users may also contact OBDMC to get help with study specific issues including clinical forms, 
data entry, data query, data sign-offs and/or uploading of regulatory and other required 
documents. For complete OBDMC contact details, click on the OBDMC Contact Information 
link that is available in the Members’ Area of the PBTC website (http://www.pbtc.org/).   
12.1.2 Method 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. A 
protocol and subject-specific CDUS “Abbreviated” data set will be submitted electronically to 
CTEP on a quarterly basis via CDUS OPEN (Oncology Patient Enrollment Network). Reports 
are due January 31, April 30, July 31, and October 31. Instructions for submitting data using the 
CDUS can be found on the CTEP website (http://ctep.cancer.gov/reporting/cdus.html). 
12.2 Collaborative Agreements Language  
Not applicable.  


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12.3 
Participant and Data Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff and 
the sponsor(s) and their agents.  This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants.  
Therefore, the study protocol, documentation, data and all other information generated will be 
held in strict confidence. No information concerning the study and the data will be released to an 
unauthorized third party without the prior written approval of the Pediatric Brain Tumor 
Consortium (PBTC).  
 
The PBTC protocol coordinators, other authorized representatives of the sponsor, regulatory 
representatives,  PBTC auditors,  representatives of the IRB or the pharmaceutical collaborator 
supplying study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study.  The clinical study site will permit access to 
such records. 
 
Source documents which are the original records of clinical findings, observations or activities in 
a clinical trial are to be maintained at each participating site.  Sites must upload all source 
documentation which supports the eligibility of the participant to the PBTC via the RAVE 
database. In the event the patient experiences unexpected events, additional source 
documentation may be requested to complete the event review. These documents may include 
but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda 
and radiographic images.   
 
Study participant study related data, which is for purposes of statistical analysis and scientific 
reporting will be transmitted to the Pediatric Brain Tumor Consortium electronically via the 
RAVE database.  This will not include the participant's contact or identifying information.  
Rather, research participants and their research data will be identified by a unique study 
identification number assigned at the time of screening or registration.  The study participant's 
contact information will be securely stored at each clinical site for internal use during the study.  
At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by local IRB and institutional regulations. 
 
The study data entry and study management systems used by clinical sites and by the PBTC will 
be secured and password protected.  At the end of the study, all study data is maintained on a 
secure server.  
 
After the study is completed, the data collected will be maintained on a server and may be used 
by other investigators, including those outside the study.  With the participant's approval and as 
approved by local IRBs, biological samples labeled only with the participant's protocol specific 
identification number will be stored at the PBTC Central Review and Biorepository and could be 
made available to other investigators for future unspecified research.  Investigators conducting 
future studies will not have access to the key for stored data collected while the participant is on 
study.  Clinical data will be de-identified before it is shared with other investigators.  
 
 


NCI Protocol#: PBTC-042 
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If the participant agrees to submit a repository sample, those samples contain genetic information 
that may be used for research related to brain tumors and their treatment.  They may also be used 
to develop tests/assays to improve diagnosis and treatment of these diseases in the future.  
Genetic research may consist of the analysis of one or more genes or the analysis of genetic 
markers throughout the genome.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13 STATISTICAL CONSIDERATIONS 
13.1 Evaluability  
13.1.1 Evaluability for DLT Assessment 
Patients who receive at least one dose of the study drug and are taken off treatment for toxicity 
during the first course (dose-finding period) are evaluable for estimating the MTD. Similarly 
patients who have to go off treatment due to inability to de-escalate following toxicity because of 
BSA restrictions are also evaluable for DLT assessment and for estimating the MTD. 
 
Patients who receive approximately 85% (17 or more doses) of prescribed therapy during the 
dose-finding period but who progress prior to completing the course may be considered 
evaluable for estimating the MTD, as long as no additional anti-cancer therapy or supportive care 
that would confound the interpretation of any observed toxicity or side effect is given. Patients 
must have completed all of the clinical and laboratory monitoring requirements specified by the 
protocol up to the time of disease progression for them to be considered evaluable for MTD. 
 
Patients who have completed all therapy during the dose-finding period but who failed to comply 
with all the specified clinical and laboratory monitoring requirements for the first course will be 
considered inevaluable for estimating the MTD and replaced. 
 
Patients who receive less than 17 doses  of the protocol specified therapy and who go off 
treatment for reasons other than toxicity (e.g. progressive disease, withdrawal of consent etc.) 
during the dose finding period will be considered inevaluable for estimating the MTD and  will 
be replaced. However as noted above, patients who go off treatment due to inability to de-
escalate following toxicity as a result of BSA restrictions are evaluable. 
13.1.2 Evaluability for preliminary evidence of response 
All eligible patients who received at least one dose of the study drug will be evaluable for 
response assessment.  
 
13.2 Study Design/Endpoints 
This is a phase I study and we will use the Rolling-6 design for dose finding.   
Since myelosuppression is the predominant side effect of this agent, the phase I study will first 
evaluate the toxicities in children who have not been heavily pre-treated previously. Once MTD 
has been established in this cohort of patients, consideration will be given to expanding the trial 
to include those who have received intensive cytotoxic therapy including myeloablative 
chemotherapy +/- craniospinal irradiation.  
 
As of version 4 and following the declaration of MTD in Stratum I, we will initiate enrollment in 
Stratum II for heavily pre-treated patients. The initial treatment dose for these patients will be 
one dose level below the MTD in stratum I and escalation to the MTD of stratum I will be 
pursued, if the initial dose level is well tolerated.  
 
Rolling-6 Design  
A ”Rolling-6” Phase I design will be used to estimate the maximum tolerated dose (MTD), 
where dose escalations are planned in cohorts of two-six patients. No intra-patient escalation will 


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be allowed. The same algorithm will be used in both strata I and II but will proceed 
independently. The maximum dose to be studied in Stratum II will be the MTD for Stratum I. 
 
Skolnik et al recently introduced the Rolling-6 design,31 motivated by the observation that most 
pediatric Phase I trials in oncology have not produced excessive toxicities. A possible 
explanation for this could be that pediatric studies are often preceded by adult trials and the 
knowledge gained in the latter is utilized towards ensuring safety in the former. The Rolling-6 
design aims to shorten the duration of pediatric Phase I trials by minimizing the time the trial 
would be closed to accrual for toxicity monitoring. This is achieved by enrolling anywhere from 
2 to 6 patients at a dose level without requiring that the DLT status of the patients already 
assigned to the same dose level are known, reducing the number of patients who would be turned 
away due to unavailability of open slots. The simulations in Skolnik et al. as well as PBTC’s 
own simulations indicate that this approach decreases the duration of a Phase I trial compared to 
the traditional method without increasing the overall incidence of toxicity. 
 
Dose Escalation/De-Escalation Rules 
The Rolling-6 design allows for accrual of two to six patients concurrently onto a dose level. 
Decisions as to which dose level to enroll a patient are based on the number of patients currently 
enrolled and evaluable, the number of patients experiencing dose-limiting toxicities (DLT), and 
the number of patients still at risk of developing a DLT at the time of new patient entry. Dose 
escalation occurs if 0 of 3-6 or no more than 1 of 6 evaluable patients experience a DLT while 
being treated at a dose level; otherwise if 2 of 2-6 patients experience DLTs the dose is declared 
too toxic and thus above the MTD. Once a dose is determined to be too toxic, further dose 
escalation is not allowed. The MTD is empirically defined as the highest dose level at which six 
patients have been treated with at most one patient experiencing a DLT and the next higher dose 
level has been determined to be too toxic.  
 
The following table enumerates all possible scenarios and describes escalation/de-escalation 
rules for a rolling 6 design. 
 
 
Dose Escalation/De-Escalation Rules for the Rolling-6 Design 
 
 
 
 
Decision when Next Patient is 
Enrolled 
# Pts. 
Enrolled 
# Pts. 
with 
DLTs 
# Pts. w/o 
DLT 
# Pts. 
with Toxicity 
Data Pending 
Not at the 
Highest 
Dose Level 
At the 
Highest 
Dose Level 
2 
0, 1 
Any 
Any 
Stay 
Stay 
2 
2 
0 
0 
De-escalate 
De-escalate 
3 
0 
0, 1, 2 
3, 2, 1 
Stay 
Stay 
3 
0 
3 
0 
Escalate 
Stay 
3 
1 
0, 1, 2 
2, 1, 0 
Stay 
Stay 
3 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 
4 
0 
0, 1, 2, 3 
4, 3, 2, 1 
Stay 
Stay 


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4 
0 
4 
0 
Escalate 
Stay 
4 
1 
0, 1, 2, 3 
3, 2, 1, 0 
Stay 
Stay 
4 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 
5 
0 
0, 1, 2, 3, 4 
5, 4, 3, 2, 1 
Stay 
Stay 
5 
0 
5 
0 
Escalate 
Stay 
5 
1 
0, 1, 2, 3, 4 
4, 3, 2, 1, 0 
Stay 
Stay 
5 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 
6 
0 
0, 1, 2, 3, 4 
6, 5, 4, 3, 2 
Suspend 
Suspend 
6 
0 
5, 6 
1, 0 
Escalate 
MTD not determined 
6 
1 
0, 1, 2, 3, 4 
5, 4, 3, 2, 1 
Suspend 
Suspend 
6 
1 
5 
0 
Escalate 
MTD not determined 
6 
≥ 2 
Any 
Any 
De-escalate 
De-escalate 
 
Based on the above-outlined escalation rules, if dose level 1 is found to be too toxic in either 
stratum, then accrual to that stratum will be suspended and the merits of amending or closing the 
stratum permanently will be reconsidered. On the other hand, if the maximum dose level 
proposed for the study is deemed to be safe, then the MTD will not have been determined and 
consideration may be given to investigate higher dose levels. Alternatively, the highest dose 
level may be recommended as the Phase II dose.  
 
Once the MTD has been estimated or the recommended Phase II dose has been determined, 6 
additional patients will be treated at that dose level to better describe the toxicity profile of the 
agent. If the number of toxicities observed in the expansion cohort suggests that the initial 
estimate of the MTD is too toxic then we will consider de-escalating to a lower dose level and 
treating additional patients at that level including an expansion cohort in an effort to estimate the 
phase II recommended dose. 
13.3 Sample Size/Accrual Rate 
Projected Accrual Rages and Study Duration 
Though it is difficult to come up with a precise estimate for recurrent pediatric brain tumor 
patients, we are estimating that up to 30% of patients screened will be Rb1 negative as measured 
by IHC and thus will not be eligible for this trial. The maximum sample size for stratum I is 24 
eligible and evaluable patients if all 3 dose levels are studied and taking into account the 
expansion cohort at the MTD (barring excessive toxicities at the expansion cohort). Hence we 
may need to screen up to 35 patients in order to enroll 24 eligible patients in stratum I.  
 
Based on the available information as of version 4.0, dose level 3 will not be studied in Stratum 
II and thus with two possible dose levels to be studied, the maximum number of patients to be 
enrolled on Stratum II is 18 (barring excessive toxicities at the expansion cohort). Though less 
information is available about the potential patient cohort for stratum II, if we assume that 30% 
of patients screened will be Rb1 negative as measured by IHC, then we may have to screen 25 
patients in order to be able to enroll 18 eligible and evaluable patients.   
 
As of version 8.0, 25 patients had been enrolled on this study; 21 in stratum I and 4 in stratum II. 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
For stratum I, the MTD has been determined as dose level 2 (75 mg/m2/day) and this stratum has 
been closed to accrual. Accrual for stratum II was recently initiated at 50 mg/m2/day, which is 
one dose level below the stratum I MTD. Four patients have been enrolled at this dose level to 
date. The intent is to either determine a new MTD for this stratum which is lower than 75 
mg/m2/day or establish that the stratum I MTD is also safe in this patient cohort. The accrual to 
the trial is ongoing.  
 
Considering that there are always patients who enroll on Phase I trials but are not evaluable for 
dose finding we may need to screen as many as 55 patients in total for both strata. 
 
The accrual rate for most of our Phase I trials open to all recurrent patients is typically 2-3 
patients/month. Considering that eligibility to this study will be limited to patients with available 
tissue for IHC analysis and among those only to patients with Rb1 + tumors, accrual rate is 
estimated to be 1-2 eligible patients per month per stratum. Hence we expect to complete accrual 
to each stratum within 1-2 years of initiating enrollment. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
5 
+ 
6 
= 
11 
Not Hispanic or Latino 
22 
+ 
22 
= 
44 
Ethnic Category: Total of all subjects 
27 
+ 
28  
= 
55 
 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
3 
+ 
3 
= 
6 
Black or African American 
6 
+ 
7 
= 
13 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
18 
+ 
18 
= 
36 
Racial Category: Total of all subjects 
27 
 + 
28 
 = 
55 
 
13.4 Analysis of the Adverse Event Data: 
All patients who receive at least 1 dose of protocol therapy will be included in the safety 
analyses. Adverse event data will be summarized in stratum specific tables which will 
incorporate dose, attribution as well as grade information.  
13.5 Data analysis plan for the secondary objectives: 
Any objective responses (PR+CR) which may be observed in this trial will be described by dose 
and by histology. We will also report prolonged disease stabilizations in a descriptive fashion. 
 
The biology and PD/PG studies are optional in this trial and thus data will be available only from 
a subset of patients who are likely to represent a variety of histologies. The data generated as part 
of these correlative studies will be described and summarized in an exploratory fashion via 
summary statistics and frequency tables as appropriate. 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
13.6 Statistical Analysis of Pharmacokinetics 
Plasma drug concentrations and pharmacokinetic parameters will be presented in tabular and 
graphical form. Pharmacokinetic parameters of interest, such as apparent volume of the central 
compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance 
(CL/F), and area under the plasma concentration time curve (AUC) will be estimated using 
compartmental methods. Dose proportionality in pharmacokinetic parameters will be 
investigated by performing one-way analysis of variance (ANOVA) on dose-normalized 
parameters. 
  
In addition to estimating individual pharmacokinetic parameters, we will also estimate the 
population parameters using nonlinear mixed effects modeling methods (NONMEM). This 
method estimates the population parameters and both the inter- and intra-subject variability. 
Once the population parameters and corresponding covariance matrix are estimated, individual 
estimates can be obtained using post hoc analysis. 
 
Because this is a Phase I study, most patients will be treated at very low doses of the agent and 
will have various diseases; thus, observations of objective responses are expected to be rare. In 
this setting, correlations of copy number variations of various cell cycle proteins and clinical 
outcome will be reported descriptively. 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
14 REFERENCES 
 
1. 
Pfister S, Remke M, Toedt G, et al. Supratentorial primitive neuroectodermal tumors of 
the central nervous system frequently harbor deletions of the CDKN2A locus and other 
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Sep 2007;46(9):839-851. 
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Li M, Lockwood W, Zielenska M, et al. Multiple CDK/CYCLIND genes are amplified in 
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Schwartz GK, LoRusso PM, Dickson MA, et al. Phase I study of PD 0332991, a cyclin-
dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer. 
Jun 7 2011;104(12):1862-1868. 
4. 
Vaughn DJ, Flaherty K, Lal P, et al. Treatment of growing teratoma syndrome. The New 
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Dubuc AM, Northcott PA, Mack S, Witt H, Pfister S, Taylor MD. The genetics of 
pediatric brain tumors. Curr Neurol Neurosci Rep. May 2010;10(3):215-223. 
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Faria C, Miguéns J, Antunes JL, et al. Pediatric brain tumors: genetics and clinical 
outcome. Journal of Neurosurgery: Pediatrics. 2010;5(3):263-270. 
7. 
Ivanchuk SM, Rutka JT. The cell cycle: accelerators, brakes, and checkpoints. 
Neurosurgery. Mar 2004;54(3):692-699; discussion 699-700. 
8. 
Cen L, Carlson BL, Schroeder MA, et al. p16-Cdk4-Rb axis controls sensitivity to a 
cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro 
Oncol. Jul 2012;14(7):870-881. 
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Paugh BS, Broniscer A, Qu C, et al. Genome-wide analyses identify recurrent 
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10. 
Warren KE, Killian K, Suuriniemi M, Wang Y, Quezado M, Meltzer PS. Genomic 
aberrations in pediatric diffuse intrinsic pontine gliomas. Neuro Oncol. Mar 
2012;14(3):326-332. 
11. 
Grill J, Puget S, Andreiuolo F, Philippe C, MacConaill L, Kieran MW. Critical oncogenic 
mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma. Pediatr Blood 
Cancer. Apr 2012;58(4):489-491. 
12. 
Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-
grade gliomas reveals key differences with the adult disease. Journal of clinical oncology 
: official journal of the American Society of Clinical Oncology. Jun 20 2010;28(18):3061-
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13. 
Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and 
chromatin 
remodelling 
genes 
in 
paediatric 
glioblastoma. 
Nature. 
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9 
2012;482(7384):226-231. 
14. 
Raabe EH, Lim KS, Kim JM, et al. BRAF Activation Induces Transformation and Then 
Senescence in Human Neural Stem Cells: A Pilocytic Astrocytoma Model. Clinical 
Cancer Research. June 1, 2011 2011;17(11):3590-3599. 
15. 
Korshunov A, Witt H, Hielscher T, et al. Molecular staging of intracranial ependymoma 
in children and adults. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. Jul 1 2010;28(19):3182-3190. 


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16. 
Rajaram V, Leuthardt EC, Singh PK, et al. 9p21 and 13q14 dosages in ependymomas. A 
clinicopathologic study of 101 cases. Modern pathology : an official journal of the 
United States and Canadian Academy of Pathology, Inc. Jan 2004;17(1):9-14. 
17. 
Mendrzyk F, Radlwimmer B, Joos S, et al. Genomic and protein expression profiling 
identifies CDK6 as novel independent prognostic marker in medulloblastoma. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. Dec 1 
2005;23(34):8853-8862. 
18. 
Parsons DW, Li M, Zhang X, et al. The genetic landscape of the childhood cancer 
medulloblastoma. Science. Jan 28 2011;331(6016):435-439. 
19. 
Jones DT, Jager N, Kool M, et al. Dissecting the genomic complexity underlying 
medulloblastoma. Nature. Aug 2 2012;488(7409):100-105. 
20. 
Kieran MW, Roberts CW, Chi SN, et al. Absence of oncogenic canonical pathway 
mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer. Dec 15 
2012;59(7):1155-1157. 
21. 
Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 
by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol 
Cancer Ther. Nov 2004;3(11):1427-1438. 
22. 
Flaherty KT, Lorusso PM, Demichele A, et al. Phase I, dose-escalation trial of the oral 
cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule 
in patients with advanced cancer. Clin Cancer Res. Jan 15 2012;18(2):568-576. 
23. 
Dean JL, McClendon AK, Hickey TE, et al. Therapeutic response to CDK4/6 inhibition 
in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle. Jul 15 
2012;11(14):2756-2761. 
24. 
Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor 
responses by PD0332991 in patients with mantle cell lymphoma. Blood. May 17 
2012;119(20):4597-4607. 
25. 
Michaud K, Solomon DA, Oermann E, et al. Pharmacologic inhibition of cyclin-
dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial 
xenografts. Cancer Res. Apr 15 2010;70(8):3228-3238. 
26. 
Huillard E, Hashizume R, Phillips JJ, et al. Cooperative interactions of BRAFV600E 
kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for 
rational therapy. Proceedings of the National Academy of Sciences of the United States of 
America. May 29 2012;109(22):8710-8715. 
27. 
Aoki Y, Hashizume R, Ozawa T, et al. An experimental xenograft mouse model of 
diffuse pontine glioma designed for therapeutic testing. Journal of neuro-oncology. May 
2012;108(1):29-35. 
28. 
Finn RS CJ, Lang I, et al. Results of a randomized phase 2 study of PD0332991, a cyclin-
dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs. letrozole alone 
for first-line treatment of ER+/HER2- advanced breast cancer (BC). Cancer Res. 
2012;72:S1-6. 
29. 
K. E. Parrish RKM, W. F. Elmquist. Mechanisms Limiting the Brain Distribution of 
Palbociclib (PD0332991). AAPS. 2013. 
30. 
Goldhoff P, Clarke J, Smirnov I, et al. Clinical stratification of glioblastoma based on 
alterations in retinoblastoma tumor suppressor protein (RB1) and association with the 
proneural subtype. J Neuropathol Exp Neurol. Jan 2012;71(1):83-89. 
31. 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
pediatric phase I trials: the rolling six design. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. Jan 10 2008;26(2):190-195. 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
 
Appendix A  
Performance Scales 
 
MODIFIED LANSKY SCORE (Score as 0 - 100) 
A.  Normal Range 
100 = Fully active 
90 = Minor restrictions in physically strenuous play 
80 = Restricted in strenuous play, tires more easily, otherwise active 
 
B.  Mild to moderate restriction 
70 = Both greater restrictions of and less time spent in active play 
60 = Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 = Considerable assistance required for any active play; full able to engage in quiet play 
 
C.  Moderate to severe restriction 
40 = Able to initiate quiet activities 
30 = Needs considerable assistance for quiet activity 
20 = Limited to very passive activity initiated by others e.g. TV) 
10 = Completely disabled, not even passive play 
  0 = Unresponsive, coma 
 
KARNOFSKY SCALE 
100 = Normal; no complaints 
90 = Able to carry on normal activities; minor signs or symptoms of disease 
80 = Normal activity with effort 
70 = Cares for self.  Unable to carry on normal activity or to do active work 
60 = Requires occasional assistance but able to care for most of his/her needs 
50 = Requires considerable assistance and frequent medical care 
40 = Disabled; requires special care and assistance 
30 = Severely disabled; hospitalization indicated though death not imminent 
20 = Very sick.  Hospitalization necessary.  Active support treatment necessary. 
10 = Moribund 
  0 = Dead 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
Appendix B  
Medications that may cause QTc Prolongation 
 
The following table presents a list of drugs that may prolong the QTc.  Patients on these 
medications are excluded from the study.   
 
 
 
Compound 
 
Compound Half Life 
Possible 
Washout 
Period - 
Hours 
Possible 
Washout 
Period - Days 
Alfuzocin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
 
4 
Amiodarone (cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hr (26-64) 
 
10 
Chloral hydrate 
Readily converted to Trichloroethanol (active 
metabolite T1/2=7-10 hour) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
7 
Cisapride 
6 – 12 hour, up to 20 hour 
60 
 
Clarithromycin 
• 
Non linear PK3-4 hr (250mg Q12) 
5-7 hr (500mg Q12) 
36 
 
Cloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
> 24 hours, wide interpatient variability 
 
 
Disopyramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hr 
48 
 
Dolesetron 
8.1 hr 
 
 
Domperidone 
7-8 hr 
48 
 
Doxepin* 
> 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Erythromycin 
* Each salt form has different Half life* 
 
 
Felbamate 
20-23 hr 
 
5 
Flecainide 
20 hr (12-27) 
 
5 
Foscarnet  
87.5+/-41.8 hours 
*distribution and release from bone* 
 
20 
Fosphenytoin 
12-29 hr 
 
6 
Gatifloxacin 
7-14 hr 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hr 
 
3 
Halofantrine 
6-10 days ( variable among individual) 
 
45 
Haloperidol 
18 +/-5 hr 
 
5 
Ibutilide 
6 hours (2-12) * variable among subject* 
36 
 
Imipramine* 
> 24 hours, wide interpatient variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isradipine 
8 hours ( multiple metabolites) 
48 
 
Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active metabolite 
2.6 day for LAAM, 2 day for nor-LAAM, 4 day for 
dinor-LAAM 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
Compound 
 
Compound Half Life 
Possible 
Washout 
Period - 
Hours 
Possible 
Washout 
Period - Days 
Lithium 
24 hour (10-50) 
 
7 
Mesoridazine 
24-48 hours ( animal study) 
 
10 
Methadone 
15-30 hours 
 
7 
Moexipril/HCTZ 
2-9 hour (include active metabolite) for moexipril; 
5.6-14.8 hours for HCTZ  
48 
 
Moxifloxacin 
12 +/-1.3 hours 
Naratriptan 
6 hours 
36 
 
Nicardipine 
~ 2 hour post IV infusion 
12 
 
Nortriptyline* 
> 24 hours, wide interpatient variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4+/-1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3-4 hour for PA and NAPA (active metabolite) 
24 
 
Protiptyline* 
> 24 hours, wide interpatient variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3-4 hours in children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor metabolizer) 
9-hydroxyrisperidone (active metabolite) T ½ =21-30 
hours (extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours ( only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
~34 hours in healthy; ~19 hours in Kidney transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hr 
24 
 
Thioridazine 
20-40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenifil 
4 to 5 hours 
 
 
Venlaflaxine 
5 +/-2 hours for parent comp. 
11+-2 hours for OVD (active metabolite) 
60 
 
Voriconizole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hr 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Appendix C  
Potential Drug Interactions with PD-0332991 (palbociclib;  
IBRANCE) 
 
This appendix is a partial list of concomitant medications that should be avoided, if possible.  
Drugs that are known to be moderate to strong inhibitors and/or inducers of CYP3A and PPIs are 
listed below. Strong CYP3A inducers/inhibitors are prohibited and moderate inducers/inhibitors 
are not recommended. PPIs are also prohibited.  
 
 
Inhibitors of CYP3A 
Ketoconazole 
Miconazole 
Itraconazole 
Posaconazole 
Clarithromycin 
Erythromycin 
Tilithromycin 
Nefazodone 
Diltiazem 
Verapamil 
Indinavir 
Saquinavir 
Ritonavir 
Nelfinavir 
Lopinavir 
Atazanavir 
Amprenavir 
Fosamprenavir 
Grapefruit Juice 
 
 
 
 
 
Inducers of CYP3A 
Phenytoin 
Carbamazepine 
Rifabutin 
Rifapentin 
Clevidipine 
Phenobarbital 
Rifampin 
St. John’s Wort 
 
 
 
Proton Pump Inhibitors (PPI) 
Rabeprazole 
Omeprazole 
Pantoprazole 
Lansoprazole 
Esomeprazole 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Appendix D  
Dosing Tables for PD-0332991 (palbociclib; IBRANCE) 
 
 
Dose Level  
50 mg/m2/day 
Total Daily 
Dose (mg) 
BSA Range 
 Capsules Required 
low 
high 
75 mg 
100 mg 
125 mg 
75 
1.20 
1.75 
1 
0 
0 
100 
1.76 
2.25 
0 
1 
0 
125 
2.26 
2.50 
0 
0 
1 
 
 
 
Dose Level  
75 mg/m2/day 
Total Daily 
Dose (mg) 
BSA Range 
 Capsules Required 
low 
high 
75 mg 
100 mg 
125 mg 
75 
0.93 
1.16 
1 
0 
0 
100 
1.17 
1.50 
0 
1 
0 
125 
1.51 
1.83 
0 
0 
1 
 
150 
1.84 
2.16 
2 
0 
0 
 
175 
2.17 
2.49 
1 
1 
0 
 
200 
2.50 
2.50 
0 
2 
0 
 
 
 
Dose Level  
95 mg/m2/day 
Total Daily 
Dose (mg) 
BSA Range 
 Capsules Required 
low 
high 
75 mg 
100 mg 
125 mg 
75 
0.70 
0.92 
1 
0 
0 
100 
0.93 
1.16 
0 
1 
0 
125 
1.17 
1.44 
0 
0 
1 
 
150 
1.45 
1.71 
2 
0 
0 
 
175 
1.72 
1.97 
1 
1 
0 
 
200 
1.98 
2.23 
0 
2 
0 
 
225 
2.24 
2.50 
0 
1 
1 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Appendix E  
Patient’s Diary 
 
 
 
PATIENT’S MEDICATION DIARY 
 
Today’s date _____________________ 
Agent:  PD-0332991 (palbociclib; IBRANCE) 
Patient Name____________________ (initials acceptable)  
 Patient Study ID ______________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take PD-0332991 (IBRANCE) capsules by mouth with food and use water to swallow the whole 
capsule (s). 
 
Dose:                        Take ________# of capsules _____________ daily. 
3. 
Record the date, the number of capsules that you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please bring this form and your bottles of PD-0332991 (IBRANCE) when you return for each 
appointment. 
 
Day 
 
Date 
 
Time of 
dose  
# of capsules taken 
Comments 
 75 mg 
100 mg 
125 mg 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
Patient’s signature________________________________________________________________ 
 
 
CTEP-assigned Protocol #_PBTC-042___ 
 
Local Protocol # PBTC-042 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment _______________________________________________________________  
2. Date patient was removed from study ________________________________________________________________  
3. Patient’s planned total daily dose ___________________________________________________________________  
4. Total number of  capsules taken this month  ___________________________________________________________  
5. Physician/Nurse/Data Manager’s Signature  ___________________________________________________________  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
Appendix F  Patient Drug Information Handout and Wallet Card 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the 
patient at the time of enrollment.  Use or modify the text as appropriate for the study agent, so 
that the patient is aware of the risks and can communicate with their regular prescriber(s) and 
pharmacist.  A convenient wallet-sized information card is also included for the patient to clip 
out and retain at all times.] 
 
The patient ____________________________ is enrolled on a clinical trial PBTC-042 using 
PD-0332991 (IBRANCE).   This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
PD-0332991 (IBRANCE) interacts with many drugs that are processed by your liver.  Because 
of this, it is very important to tell your study doctors about all of your medicine before you start 
this study.  It is also very important to tell them if you stop taking any regular medicine, or if you 
start taking a new medicine while you take part in this study.  When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug 
store (over-the-counter remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
PD-0332991 (IBRANCE) interacts with a certain specific enzyme in your liver.  
• The enzyme in question is CYP3A4/5.  PD-0332991 (IBRANCE) is broken down by 
this enzyme in order to be cleared from your system. The dose of this drug that you are 
taking assumes that these enzymes are working normally. 
• Certain drugs may reduce the activity of CYP3A4/5, which can increase the amount of 
active drug in your system.  This increases your chances of experiencing harmful side 
effects.  Other drugs might increase the activity of CYP3A4/5, reducing the level of 
active drug in your system and making it less effective. 
• PD-0332991 (IBRANCE) must be used very carefully with such drugs; it is therefore 
vitally important that you provide your study doctor with a complete list of your 
medications.  Before you begin the study, your study doctor will work with your regular 
prescriber to switch any medicines that are considered “strong inhibitors or inducers of 
CYP3A4/5.” 
• Once the study begins, you and your healthcare providers must be very careful about 
adding or removing any drugs in this category.  Your prescribers should look at the web 
site http://medicine.iupui.edu/clinpharm/ddis/main-table/, consult a medical reference, or 
contact your study doctor to see if any medicine they want to prescribe is on a list of 
drugs to avoid. 
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 


NCI Protocol#: PBTC-042 
Version Date: 28 June 2018 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.  
 
Be careful:  
➢ If you take acetaminophen regularly:  You should not take more than 4 
grams a day if you are an adult or 2.4 grams a day if you are older than 65 
years of age.  Read labels carefully!  Acetaminophen is an ingredient in 
many medicines for pain, flu, and cold. 
➢ If you drink grapefruit juice or eat grapefruit:  Avoid these until the study  
     is over.  
➢ If you take herbal medicine regularly:  You should not take St. John’s wort 
while you are taking PD-0332991 (IBRANCE). 
 
Other medicines can be a problem with your study drug.  
▪ You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
▪ Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is Physician’s name and he or she can be contacted at 
Physician’s telephone number. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial PBTC-042 using  PD- 
0332991 (IBRANCE).   
PD-0332991 (IBRANCE) interacts with drugs that are 
processed by your liver.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you 
start taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, 
nurse practitioner, pharmacist) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement. 
PD- 0332991 (IBRANCE) interacts with a specific liver enzyme 
called CYP3A4/5, and must be used very carefully with other 
medicines that interact with this enzyme.  
➢ Before you start the study, your study doctor will work with 
your regular prescriber to switch any medicines that are 
considered “strong inducers or inhibitors of CYP3A4/5”. 
➢ Before prescribing new medicines, your regular prescribers 
should go to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for 
a list of drugs to avoid, or contact your study doctor.   
 
➢ Your study doctor’s name is _________________________ 
and can be contacted at _________________________