Preoperative Palbociclib in Patients With DCIS of the Breast That Are Candidates for Surgery
Phase: PHASE2
Conditions: DCIS
Sponsor: Georgetown University

 
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PROTOCOL 
 
TITLE: Preoperative palbociclib in patients with DCIS of the breast that are candidates for surgery 
 
PROTOCOL NUMBER: WI223281 
 
EUDRACT NUMBER: 2014-000156-28 
 
IND NUMBER: 137,811 IND EXEMPT 
 
TEST PRODUCT: Palbociclib (Ibrance®)  
 
INVESTIGATIONAL PRODUCT SUPPLIER: Pfizer Inc 
 
FUNDING: Pfizer Inc 
 
ClinicalTrials.gov IDENTIFIER: NCT03535506 
 
PROTOCOL VERSION: 1.2 
 
PROTOCOL VERSION DATE: 01/20/2022 
 
PRINCIPAL INVESTIGATOR:  
Candace Mainor, MD 
Medstar Georgetown University Hospital and  
Lombardi Comprehensive Cancer Center 
3800 Reservoir Road 
Washington, DC 20007 
 
 
 
 
 
 

 
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PROTOCOL SIGNATURE PAGE 
 
 
TITLE: Preoperative palbociclib in patients with DCIS of the breast that are candidates for surgery 
 
PROTOCOL NUMBER: WI223281 
 
EUDRACT NUMBER: 2014-000156-28 
 
IND NUMBER: 137,811 IND EXEMPT  
 
 
Declaration of Investigator 
I confirm that I have read the above-mentioned protocol and its attachments. I agree to conduct the 
described trial in compliance with all stipulations of the protocol, all applicable regulations, ICH Good 
Clinical Practice (GCP) and Declaration of Helsinki. 
 
 
-------------------------------------------------  
 
 
-------------------------------------------------- 
First Name, Last Name   
 
 
 
Date, Signature 
 

 
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Table of Contents 
 
PROTOCOL SYNOPSIS .................................................................................................................................... 7 
1. 
BACKGROUND ..................................................................................................................................... 11 
1.1 Background on Ductal Carcinoma in Situ (DCIS) ............................................................................... 11 
1.2 Background on Palbociclib ................................................................................................................ 13 
1.2.1 Cdk4, Cdk6, Rb ........................................................................................................................... 13 
1.2.2 Palbociclib .................................................................................................................................. 13 
1.2.3 Palbociclib in Advanced HER2-negative Breast Cancer ............................................................. 13 
1.2.4 Palbociclib in Early HER2-negative Breast Cancer ..................................................................... 14 
1.2.5 Palbociclib clinical toxicity and safety ........................................................................................ 14 
1.3 Study Rationale ................................................................................................................................. 17 
1.3.1 Preclinical experience on CDK4/6 inhibition and DCIS .............................................................. 17 
1.3.2 Palbociclib as potential treatment for DCIS ............................................................................... 18 
2. 
OBJECTIVES AND OUTCOME MEASURES ............................................................................................ 19 
2.1 Hypothesis ......................................................................................................................................... 19 
2.2 Objectives.......................................................................................................................................... 19 
2.2.1 Primary Objectives ..................................................................................................................... 19 
2.2.2 Secondary Objectives ................................................................................................................. 19 
2.3 Outcome Measures ........................................................................................................................... 19 
3. 
STUDY DESIGN..................................................................................................................................... 20 
3.1 Description of Study .......................................................................................................................... 20 
3.1.1 Overview of Study Design .......................................................................................................... 20 
3.2 End of Treatment .............................................................................................................................. 23 
3.3 End of Study ...................................................................................................................................... 23 
3.3.1 End of Study Visit ....................................................................................................................... 24 
3.3.2 Managing Patients Who Never Received Protocol Treatment .................................................. 24 
3.3.3 Patients Lost to Follow Up ......................................................................................................... 24 
3.4 Rationale for Study Design ................................................................................................................ 24 
3.4.1 Rationale for Test Product Dosage (Palbociclib) ........................................................................ 24 
3.4.2 Rationale for Choice of Regimen ............................................................................................... 25 
4. MATERIALS AND METHODS .................................................................................................................... 25 

 
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4.1 Patients ............................................................................................................................................. 25 
4.1.1 Inclusion Criteria ........................................................................................................................ 25 
4.1.2 Exclusion Criteria ........................................................................................................................ 27 
4.2 Registration Procedures .................................................................................................................... 28 
4.2.1 Study Site ................................................................................................................................... 29 
4.2.2 Study Coordinators and Pharmacists ......................................................................................... 29 
4.2.3 Patient Enrollment ..................................................................................................................... 29 
4.3 Study Treatment ............................................................................................................................... 31 
4.3.1 Formulation, Packaging, and Handling ...................................................................................... 31 
4.3.2 Dosage, Administration, and Compliance .................................................................................. 33 
4.4 Concomitant Therapy ....................................................................................................................... 34 
4.4.1 Surgery ....................................................................................................................................... 34 
4.4.2 Radiotherapy .............................................................................................................................. 34 
4.4.3 Hormone Therapy ...................................................................................................................... 34 
4.4.4 Permitted Therapy ..................................................................................................................... 35 
4.4.5 Prohibited Therapy .................................................................................................................... 35 
4.5 Study Assessments ............................................................................................................................ 35 
4.5.1 Pre-Screening phase .................................................................................................................. 36 
4.5.2 Screening phase ......................................................................................................................... 36 
4.5.3 Treatment phase ........................................................................................................................ 38 
4.5.4 Pre-Surgery phase ...................................................................................................................... 39 
4.5.5 Surgery ....................................................................................................................................... 39 
4.5.6 Follow up phases  End of Study Visit and Long Term Follow Up ............................................. 39 
4.6 Patient and Study Discontinuation ................................................................................................... 39 
5. ASSESSMENT OF SAFETY ......................................................................................................................... 40 
5.1 Safety Plan......................................................................................................................................... 40 
5.1.1 Dose Delays and Modifications for Palbociclib .......................................................................... 40 
5.1.2 Treatment discontinuation ........................................................................................................ 40 
5.1.3 
Management of Specific Adverse Events ............................................................................ 40 
5.1.4 Pregnancy and Contraception Use............................................................................................. 41 
5.1.5 Lactation ..................................................................................................................................... 41 
5.1.6 Geriatric Use .............................................................................................................................. 41 

 
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5.2 Safety Parameters and Definitions ................................................................................................... 42 
5.2.1 Adverse Events ........................................................................................................................... 42 
5.2.2 Serious Adverse Events (Immediately Reportable to the Sponsor) ........................................... 43 
5.2.3 Non-Serious Adverse Events of Special Interest (Immediately Reportable to the Sponsor) ..... 43 
5.2.4 Medication errors ...................................................................................................................... 43 
5.3 Methods and Timing for Capturing and Assessing Safety Parameters ............................................. 43 
5.3.1 Adverse Event Reporting Period ................................................................................................ 44 
5.3.2 Eliciting Adverse Event Information ........................................................................................... 44 
5.3.3 Assessment of Adverse Event Severity ...................................................................................... 44 
5.3.4 Assessment of Causality of Adverse Events ............................................................................... 45 
5.3.5 Procedures for Recording Adverse Events ................................................................................. 45 
5.4 Immediate Reporting Requirements ................................................................................................ 46 
5.4.1 Emergency Medical Contacts ..................................................................................................... 46 
5.4.2 Serious Adverse Events Reporting Requirements ..................................................................... 46 
5.4.3 Non-Serious Adverse Event Reporting Requirements ............................................................... 48 
5.4.4 Sponsor PI Reporting Requirements to Regulatory Authorities ................................................ 48 
5.4.5 Reporting Forms:........................................................................................................................ 49 
5.4.6 IND Annual Reports .................................................................................................................... 50 
5.4.7 Data Safety Monitoring Committee ........................................................................................... 50 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ............................................................................. 51 
6.1 Determination of Sample Size ........................................................................................................... 51 
7. DATA COLLECTION AND MANAGEMENT ................................................................................................ 51 
7.1 Data Quality Assurance ..................................................................................................................... 51 
7.2 Electronic Case Report Forms ........................................................................................................... 52 
7.3 Source Data Documentation ............................................................................................................. 52 
7.4 Retention of Records ........................................................................................................................ 52 
8. ETHICAL CONSIDERATIONS ..................................................................................................................... 53 
8.1 Institutional Review Board or Ethics Committee .............................................................................. 53 
8.2 Informed Consent ............................................................................................................................. 53 
8.3 Subject Compensation ...................................................................................................................... 54 
8.4 Confidentiality ................................................................................................................................... 54 
8.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .................................. 55 

 
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8.6 Amendments to the Protocol ........................................................................................................... 56 
8.7 Financial Disclosure ........................................................................................................................... 56 
8.8 Adherence to the Protocol ................................................................................................................ 56 
9. REQUIRED DOCUMENTATION ................................................................................................................. 57 
10. REFERENCES .......................................................................................................................................... 57 
Appendix A: Study procedures.................................................................................................................... 61 
Appendix B: Study schema .......................................................................................................................... 63 
Appendix C: Calendar for treatment planning based on surgery date for Group A patients ..................... 65 
Appendix D: Enrollment Process to Treatment Overview .......................................................................... 66 
Appendix E: Eligibility Checklist .................................................................................................................. 67 
Appendix F: Lombardi Patient Registration Form ....................................................................................... 71 
Appendix G: Eastern Cooperative Oncology Group (ECOG) Performance Status ...................................... 73 
Appendix H: Drug Supply Request Form ..................................................................................................... 74 
Appendix I: Investigational Drug Order Form (Palbociclib) ........................................................................ 75 
Appendix J: Palbociclib Diary (Group A) ...................................................................................................... 76 
Appendix K: Reportable event fax cover sheet ........................................................................................... 78 
Appendix L: Pathology Form ....................................................................................................................... 79 
Appendix M: Research Blood Sample Form ................................................................................................ 80 
 
 
 

 
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PROTOCOL SYNOPSIS 
 
Title 
Preoperative palbociclib in patients with DCIS of the breast that are 
candidates for surgery 
Study Drug
Palbociclib 
Protocol Number 
WI223281
Number of Patients 
24
Length of Study
The total duration of the study is expected to be approximately 12 months. 
Study Design
This is a feasibility study which will evaluate the effects of pre-operative 
treatment of DCIS of the breast with palbociclib. Patients with biopsy-
proven DCIS are eligible for the study.  
There will be 2 independent and unrelated study groups of 12 patients 
each, for a total of 24 patients:  
(a) Group A, of male or female patients treated with palbociclib single 
agent (n=12); 
 (b) Group B, untreated, of male or female patients who consented 
translational studies in blood, as well as diagnostic and definitive 
surgical specimen, but not the pre-operative treatment with 
palbociclib (n=12).  
Primary Objectives 
 
1)
Feasibility 
2)
Preliminary evidence of DCIS response to palbociclib: Pathologic 
changes of breast tissue comparing paired biopsies before and after 
treatment (core vs definitive surgery) from each patient.  
a)
Gross path, H&E changes, multiple biological markers (potentially 
including CDK4 and CDK6 expression, Cyclin D1 expression, P16 
expression, Ki-67 proliferation, TFF1 expression, PCNA expression) 
Secondary 
Objectives 
 
1)
Toxicities 
2)
Correlative science and tissue banking 
Inclusion Criteria 
 
Inclusion Criteria for all patients (Groups A and B) 
I.1 Signed informed consent obtained prior to any study specific 
assessments and procedures 

 
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I.2 Age 18 years 
I.3 Premenopausal and postmenopausal women or men  
I.4 Current pathologic diagnosis of DCIS of the breast of any receptor 
status; 
a) History of previous DCIS allowed provided that the patient is 
currently off systemic risk-reduction endocrine therapy; 
b) History of previous invasive breast cancer adequately treated and 
that is currently in remission and unrelated to current DCIS (based 
on primary tumor location) is allowed as long as patient is currently 
off systemic therapy for that invasive cancer for at least 4 weeks 
prior to pre-treatment biopsy (diagnostic biopsy); 
c) Patients with multifocal or multicentric lesions are allowed, as long 
as one lesion is histologically confirmed DCIS and overall clinical 
AJCC Stage I. 
I.5 A formalin-fixed paraffin-embedded (FFPE) tumor tissue block from 
diagnostic biopsy must be transmitted to MedStar Georgetown 
University Hospital Pathology Department repository and confirmation 
of receipt must be available prior to enrollment.  
I.6 Positive Rb by immunohistochemistry in the DCIS component of the 
lesion  
a) Must be performed at CLIA-approved setting (for instance, MGUH) 
b) Rb staining will be considered positive when 1+ or above (in a scale 
of 0, 1+, 2+ or 3+) 
I.7 In the absence of histologic diagnosis of DCIS, patient may undergo 
fresh biopsy for eligibility, provided: 
a) This invasive procedure is not a Fine Needle Aspiration (FNA); AND 
b) This procedure is a core biopsy, stereotactic biopsy or incisional 
biopsy of the suspicious breast lesion; AND 
c) The primary lesion is not completely resected during the procedure. 
I.8 The patient is candidate for and is willing to receive definitive surgical 
therapy for DCIS 
I.9 ECOG performance status 0-1 (Appendix G: ECOG PS scale). 
I.10 Willingness to provide a sample of tissue collected at definitive surgery 
for research. 

 
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Inclusion Criteria specific for patients enrolled on Group A 
 
I.11 
Patients must be able and willing to swallow and retain oral 
medication  
I.12 
Absolute neutrophil count (ANC)  1,500/mm3 
I.13 
Platelets  120,000/mm3 
I.14 
Hemoglobin  10g/dL 
I.15 
Total serum bilirubin  ULN; or total bilirubin  3.0 × ULN with 
direct bilirubin within normal range in patients with documented Gilbert's 
Syndrome. 
I.16 
Aspartate amino transferase (AST or SGOT) and alanine amino 
transferase (ALT or SGPT)  1.5 × institutional ULN 
I.17 
Serum creatinine within normal institutional limits or creatinine 
clearance  50 mL/min/1.73 m2 for patients with serum creatinine levels 
above institutional ULN. 
I.18 
Pregnancy must be ruled out: 
a) 
Serum or urine pregnancy test must be negative within 14 days of 
treatment start in women of childbearing potential.  
b) 
Pregnancy testing does not need to be pursued in patients who are 
judged as postmenopausal before enrollment, or who have undergone 
tubal ligation, bilateral oophorectomy, total hysterectomy 
I.19 
Willingness to undergo adequate contraception if childbearing 
potential 
a) 
Women of childbearing potential and male patients randomized 
into treatment Group A must use adequate contraception for the duration 
of protocol treatment and for 3 months after the last treatment with 
palbociclib if they are in Group A.  
b) 
Adequate contraception is defined as one highly effective form (i.e. 
abstinence, (fe)male sterilization) OR two effective forms (e.g. non-
hormonal IUD and condom / occlusive cap with spermicidal foam / gel / 
film / cream / suppository). 
There are no Inclusion Criteria specific for patients enrolled on Group B 

 
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Exclusion Criteria 
Exclusion Criteria for all patients (Groups A and B) 
E.1 
Concurrent therapy with other Investigational Products. 
E.2 
Invasive carcinoma present in the diagnostic biopsy 
Microinvasion is allowed 
E.3 
Uncontrolled intercurrent illness including (active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, diabetes, pulmonary embolism in the past 6 months, or 
psychiatric illness/social situations that would limit compliance with study 
requirements). 
E.4 
Unable to comply with study requirements 
E.5 
Hormone therapies containing estrogen, progesterone, GnRH 
agonists and antagonists within 4 weeks from diagnostic biopsy. 
E.6 
Therapy with any CDK inhibitor in the past 3 months 
 
Exclusion Criteria Specific for patients enrolled on Group A 
E.7 
History of allergic reactions attributed to compounds of chemical or 
biologic composition similar to palbociclib 
E.8 
Presence of a condition that would interfere with enteric 
absorption of palbociclib 
E.9 
Pregnant women, or women of childbearing potential without a 
negative pregnancy test (serum or urine) within 7 days prior to enrollment 
Breastfeeding must be discontinued prior to study entry (Group A 
only). 
E.10 
Patients on combination antiretroviral therapy, i.e. those who are 
HIV+ (potential for pharmacokinetic interactions or increased 
immunosuppression with palbociclib). 
E.11 
Patients receiving any medications or substances that are potent 
inhibitors or inducers of CYP3A isoenzymes within 7 days of enrollment or 
during participation on study (see Section 4.4.5 Prohibited Therapy for list 
of CYP3A inhibitors and inducers). 
E.12 
Patients with clinically significant history of liver disease, including 
viral or other known hepatitis, current alcohol abuse, or cirrhosis, etc. 
There are no Exclusion Criteria specific for patients enrolled on Group B 

 
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1. BACKGROUND 
 
1.1 Background on Ductal Carcinoma in Situ (DCIS) 
 
Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions 
confined to the breast ducts. In 2016, approximately 61,000 new cases of carcinoma in situ of the breast 
and 246,600 new cases of invasive breast cancer are expected to be diagnosed in American women1.  
With improvement in mammographic screening, the diagnosis of DCIS increased dramatically. DCIS now 
accounts for approximately 20-25% of detected breast carcinomas in screened populations2. 
Furthermore 40% of DCIS cases progress to invasive breast cancer if left untreated and the 20-year 
breast cancer-specific mortality rate following DCIS is 3.3%3. Therefore, the goal and challenge of 
therapy for DCIS is (1) to identify who needs treatment; and (2) to prevent the development of invasive 
breast cancer. Currently therapeutic approaches include surgery, radiation therapy, and adjuvant 
endocrine therapy. The key pathologic components of exam involve the following4-7: 
 
Nuclear grade (low, intermediate, or high). 
The size or extent of the lesion. 
The distance to the closest margin, including whether the margins were only focally or extensively 
involved.  
Specimen orientation to identify specific margins and allow for targeted re-excision if necessary. 
Estrogen and progesterone receptor status. 
 
The most appropriate treatment for DCIS remains uncertain. One of the greatest challenges of 
8. Prognostic 
classifications have been created in an attempt to guide therapy development, planning and delivery. 
These classifications typically include the above mentioned pathologic features as well as patient age9,10. 
Unfortunately, the classifications based on clinicopathologic characteristics and standard biomarkers are 
still imprecise in stratifying risk and potential benefit with available interventions including surgery, 
radiation and endocrine therapy11. The emergence of new efficacious and safe targeted therapies in 
oncology allows the design of trials that could help identifying unique populations of patients candidates 
for the emerging intervention 12,13.  
DCIS management: At the present time, for patients treated with mastectomy no additional therapy 
is typically recommended.  On the other hand, patients treated with lumpectomy are offered post-
lumpectomy radiation and, if estrogen and progesterone receptors are present, risk reduction endocrine 
therapy for 5 years.  The decision between mastectomy or lumpectomy, radiation and tamoxifen for 
treatment of DCIS is typically difficult for patients.  Mastectomy provides overly aggressive treatment for 
many women1. After mastectomy, disease recurrence rate is estimated at approximately 2%14-16.  
Unfortunately, when recurrent after mastectomy, it carries a high mortality rate for those who do 
relapse16.  The risk of distant metastasis seems to be significantly higher in high grade DCIS when 
compared to low grade DCIS17.  In multiple studies, younger age was found to be an independent risk 
factor for recurrence in multivariate analysis16,18. In addition, unexpected invasive carcinoma is found in 
15-25% of mastectomies performed for DCIS19. When invasive carcinoma is present at definitive surgery, 
treatment plan is updated and focuses on the higher risk lesion, involving a multidisciplinary approach. 
Approximately 70% of women with newly diagnosed DCIS are managed with breast conserving 
surgery20.  Lumpectomy has less morbidity but this is associated with a higher risk of local recurrence, 

 
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even when combined with radiation therapy, than mastectomy alone.  A recent report from a 
retrospective study of approximately 32,000 patients in the Surveillance, Epidemiology, and End Results 
(SEER) database treated with lumpectomy for DCIS indicated that adjuvant radiation was associated 
with improved breast specific survival for patients with high nuclear grade, younger age, or larger tumor 
size21. A long-term follow-up report from NSABP B 17 and B 24 randomized clinical trials for DCIS 
revealed that after 15 years, invasive ipsilateral breast tumor recurrence occurred in 19.4% of patients 
who received lumpectomy alone compared with 8.5% of patients who received lumpectomy, radiation 
and tamoxifen22.  The presence of invasive recurrence was associated with an increase in mortality risk, 
but recurrence of DCIS was not.  The overall mortality was low in patients who underwent lumpectomy. 
Among women diagnosed with DCIS, the risk of developing contralateral breast cancer or DCIS is 
approximately 3 to 10 percent23-25.  In a recent retrospective study 108,196 cases of DCIS were analyzed 
with extensive follow-up data, revealing that aggressive treatment did not reduce the number of breast 
cancer associated deaths, and highlighting the need for novel treatment strategies26. In that report, 
occurrence of invasive cancer after DCIS substantially increased the risk of cancer-related death. 
Tailored treatment for DCIS: Attempts have been made to de-escalate care for patients with very 
low risk DCIS.  To define a population in which radiation therapy could be omitted after lumpectomy, 
the Eastern Cooperative Oncology Group (E5194) investigated lumpectomy without radiation in selected 
patients (<2.5 cm of low- to intermediate-grade DCIS or <1.0 cm for high-grade DCIS)27.  Median tumor 
size was only 6 mm.  The 12-year local recurrence rate for low  or intermediate grade, or for high-grade 
DCIS was 14.4% and 24.6%, respectively.  These results support the impression that higher grade lesions 
are associated with higher risk of recurrence. A more recent approach to help determining risk for better 
treatment planning involves the use of gene expression analysis.  The Oncotype DX DCIS recurrence 
score  has also been studied as a tool for identification of patients for whom post lumpectomy radiation 
could be reasonably omitted28.  However, data regarding its suitability are still preliminary1, and again 
the assay does not identify clearly patients who will develop recurrence even treated with maximum 
current available treatment. Risk of recurrence after lumpectomy varied between 7.5% and 20.5%, 
according to assay score and use of radiation29. 
Endocrine risk reduction therapy with tamoxifen, raloxifene or aromatase inhibitors (AIs) is 
recommended for women with hormone positive DCIS. While tamoxifen has been shown to reduce the 
risk of breast cancer by 49% in women with DCIS, long-term treatment with tamoxifen does carry 
multiple risks, including increased risk of endometrial cancer and venous thrombosis, which are higher 
for women over 50yrs. Raloxifene is often better tolerated than tamoxifen; however, it appears to be 
less efficacious for prevention of invasive breast cancer in long-term follow-up30. AIs have recently been 
added to the NCCN guidelines as a risk-reduction agent. In the MAP3 trial31, exemestane decreased the 
relative risk of invasive breast cancer by 65% over 3 years but AIs carry their own risks with long-term 
use (i.e., osteoporosis, joint pain).  
Better risk stratification and more effective and tolerable treatments are needed to help prevent 
DCIS recurrence or progression of these in situ lesions into more invasive cancers. Ongoing trials 
continue to evaluate lumpectomy, radiation and endocrine therapy with tamoxifen or with an AI. This is 
the case of NSABP B-35 and IBIS II (anastrozole or tamoxifen) and CALGB 40903 (letrozole). NSABP B-43 
on the other hands evaluates the potential efficacy of trastuzumab for HER2 positive DCIS. There is no 
approved systemic risk-reducing treatment for ER/PR negative DCIS. 
Based on the above-mentioned statistics we estimate approximately 43,000 women would be 
treated with lumpectomy for DCIS each year in this country. If 15-25% of them are expected to 
experience recurrence with currently available therapies, this would represent approximately 6,500 to 
10,750 women who could have benefitted from different, newer treatments, if available, every year. 

 
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The challenges are to identify, at the time of diagnosis, the patients more likely to develop recurrence 
and subsequent morbidity, and to develop effective therapies that could prevent morbidity from 
recurrence in this higher risk population.  
 
1.2 Background on Palbociclib 
 
1.2.1 Cdk4, Cdk6, Rb 
Deregulation of the cell-cycle machinery is a fundamental hallmark of cancer progression and a 
common feature in carcinogenesis32,33. Cyclin-dependent kinases Cdk4 or Cdk6, regulate events in 
the G1 phase of the cell cycle and contribute to the phosphorylation of the retinoblastoma gene 
product (Rb). However, in cells in which the function of Rb has been compromised, Cdk4 and Cdk6 
are not associated with D cyclins, but rather with p16. Rb negative cells express high levels of p16, 
competing with D cyclins for binding to Cdk4 and Cdk6, preventing the formation of active 
complexes34. In the cell cycle, during the progression through G1, growth signals allow cyclin D to 
complex with either Cdk4 or Cdk6. This process facilitates the addition of phosphate groups to Rb. 
As the cell progresses from G1 to S, cyclin E complexes with Cdk2 and hyperphosphorylates Rb, 
with release of bound E2F. This E2F activates S-phase genes allowing cell cycle progression35. In 
tumors with intact Rb, the process of Rb phosphorylation and inactivation necessary to facilitate 
cell division is rate limited by cyclin D1 levels36. 
 
1.2.2 Palbociclib 
Palbociclib is a new, oral, highly specific small-molecule inhibitor of Cdk4 and Cdk6. Palbociclib 
potently, equally and selectively inhibits both Cdk4 and Cdk6 cyclin D1 kinase activity37. Its 
efficacy has been demonstrated in a number of Rb proficient human cancer cells, including breast 
cancer. In vitro studies have demonstrated high activity in hormone receptor positive breast 
cancer cell lines, which are the most likely to have an intact Rb pathway, especially when added to 
endocrine therapies like tamoxifen and letrozole. In addition, a study in which 18 TNBC cell lines 
were screened for sensitivity to palbocicilb in long-term clonogenic assays revealed sensitivity of 
the luminal-androgen (LAR) and mesenchymal-stem like (MSL) triple negative subsets, in particular 
in association with expression of androgen receptor (p = 0.0013), and with the absence/or low 
levels of cyclin E1 (p = 0.01)38.  
 
1.2.3 Palbociclib in Advanced HER2-negative Breast Cancer 
Palbociclib was recently approved by the FDA for use in metastatic hormone receptor positive 
breast cancer based on the results of the PALOMA-1/TRIO-18 study which found a significant 
increase in progression-free survival from 10.2 months for letrozole alone compared to 20.2 
months for palbociclib combined with letrozole39.  The PALOMA-3 trial is a phase III clinical trial 
demonstrating that among women with hormone receptor positive metastatic breast cancer, 
palbociclib combined with fulvestrant resulted in longer progression-free survival (9.2 months) 
than fulvestrant alone (3.8 months; p <.001)40. 

 
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1.2.4 Palbociclib in Early HER2-negative Breast Cancer  
Due to the success of palbociclib when combined with endocrine therapy in the metastatic setting, 
there is now growing interest in the potential use of this drug in earlier disease states. The FB-
11/PALLET trial is an ongoing phase II trial where women with early hormone receptor positive 
breast cancer receive neoadjuvant palbociclib +/- letrozole (NCT02296801). In August 2015 The 
Alliance Foundation Trials, LLC (AFT), the Austrian Breast & Colorectal Cancer Study Group 
(ABCSG), and Pfizer Inc. announced the launch of the Palbociclib Collaborative Adjuvant Study, or 
PALLAS (NCT02513394). This global Phase 3 clinical trial for patients with early-stage breast cancer 
is being conducted in conjunction with Breast International Group (BIG), German Breast Group 
(GBG), National Surgical Adjuvant Breast and Bowel Project (NSABP), and PrECOG, LLC (PrECOG). 
The PALLAS trial is evaluating whether the addition of palbociclib, to standard therapy will 
improve disease-free survival and prevent the disease from recurring. Patients treated in this 
study have hormone receptor-positive (HR+), HER2 negative breast cancer treated with curative 
intent by surgery.  
 
1.2.5 Palbociclib clinical toxicity and safety 
Palbociclib 125mg PO daily continuously for 21 days followed by 7-day rest period in combination 
with endocrine therapy is the approved schedule by FDA for treatment of patients with metastatic 
HR+HER2- breast cancer. In the studies leading to FDA approval, Palbociclib was used until disease 
progression or unacceptable toxicity (median duration of palbociclib therapy > 12 months). 
Therefore, the schedule used to treat patients with metastatic disease includes higher dose, 
longer exposure in each cycle and longer length of treatment overall than those proposed in the 
current study for DCIS patients (a single cycle of Palbociclib 100mg daily for 12 days).  
The clinical safety of Palbociclib (125 mg/day) plus Letrozole (2.5 mg/day) versus Letrozole alone 
was clinically evaluated in 160 patients with ER-positive, HER2-negative advanced breast cancer 
who received at least 1 dose of treatment in a phase II study 39. Overall this treatment 
combination is considered very well tolerated, allowing patients to carry on with personal and 
professional daily activities. Palbociclib doubled PFS when added to Letrozole, as compared to 
Letrozole alone. Dose reductions due to an adverse reaction of any grade occurred in 36% of 
patients receiving Palbociclib plus Letrozole. Permanent discontinuation associated with an 
adverse reaction occurred in 7 of 83 (8%) patients receiving Palbociclib plus Letrozole and in 2 of 
77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those 
patients receiving Palbociclib plus Letrozole included neutropenia (6%), asthenia (1%), and fatigue 
(1%). 
Palbociclib plus Letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory 
infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, 
asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse 
reactions in patients receiving Palbociclib plus Letrozole were pulmonary embolism (3 of 83; 4%) 
and diarrhea (2 of 83; 2%). An increased incidence of infections was observed in the Palbociclib 
plus Letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia has 
been reported in the Palbociclib clinical program, although no cases were observed in that study. 
 in that study by dose reductions and/or dose delay, or 

 
Protocol WI223281  Palbociclib in DCIS  Mainor 
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temporary discontinuation. 
Palbociclib plus Letrozole or Letrozole alone are listed in Table 1. 
 
Table 1. Adverse Reactions (>=10%) of Letrozole +/- Palbociclib (PALOMA trial) 39 
 
 
 
The safety of Palbociclib (125 mg/day) plus Fulvestrant (500 mg) versus placebo plus Fulvestrant 
was evaluated in another clinical trial of 517 patients with HR-positive, HER2-negative advanced or 
metastatic breast cancer who received at least 1 dose of treatment 41. Dose reductions due to an 
adverse reaction of any grade occurred in 36% of patients receiving Palbociclib plus fulvestrant. 
Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) 
patients receiving Palbociclib plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus 
fulvestrant. Adverse reactions leading to discontinuation for those patients receiving Palbociclib 
plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%). The most 
common adverse reactions 
Palbociclib plus 
fulvestrant arm were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, 
headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased 

 
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appetite, and pyrexia. The most frequently reported serious adverse reactions in patients 
receiving Palbociclib plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and 
pulmonary embolism (1%). Adverse reactions reported in patients who received Palbociclib plus 
fulvestrant or placebo plus fulvestrant in this study are listed in Table 2. 
 
Table 2. Adverse Reactions (>=10%) of Fulvestrant +/- Palbociclib (PALOMA3 trial) 41 
 
 
 
 
In a phase I study 42, palbociclib related neutropenia and thrombocytopenia occurred around day 21, the 
end of 21-day period of continuous PO daily dose in a 28-day cycle. In cycle 1, rebound of both ANC and 
platelet levels were observed during the off-drug period that continued up to day 8 of the following 
dosing cycle. 
 

 
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1.3 Study Rationale  
 
 1.3.1 Preclinical experience on CDK4/6 inhibition and DCIS 
 
Loss of the retinoblastoma tumor suppressor pathway (Rb) is one of the strongest markers of DCIS 
recurrence and progression. Preclinical studies support the development of Cdk 4/6 inhibitors in DCIS. 
Cdk4 
and 
Cdk6 
are 
very 
important 
in 
cellular 
proliferation; 
they 
phosphorylate Rb and initiate 
transition from the G1 phase to 
the S phase in the cell cycle. 
Inhibition of Cdk4 and Cdk6 
activity in an Rb-dependent 
manner 
prevents 
the 
development 
of 
invasion 
lesions43. 
Furthermore, 
immortal mammary epithelial 
cell lines with Rb knockout lead 
to invasive lesions in xenograft 
assays 
but 
Rb 
proficient 
parental cells lead to DCIS-like 
lesions43.  
In our hands, the well-established MCF-DCIS in vitro model gives well defined DCIS lesions when 
implanted subcutaneously in animals. These lesions progress to invasive disease within 3-5 weeks in this 
model44,45. Pathologic features and gene expression pattern of MCF-DCIS mimics that of human DCIS 
lesions46. The ductal lesions that develop after 3 weeks implantation of MCF-DCIS cells resemble high 
grade comedo DCIS and both 
the luminal and myoepithelial 
cell layers of the DCIS lesions 
are 
derived 
from 
the 
progenitor MCF-DCIS cells45,47. 
We 
determined 
that 
palbociclib can inhibit MCF-
DCIS proliferation in vitro (Fig 
1). The IC50 was approximately 
100 
nM, 
at 
which 
concentration 
there 
was 
significant 
change 
in 
morphology of the cells. We 
also observed a significant 
decrease in Cdk2 and PCNA 
expression in the cells with low 

 
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doses of palbociclib treatment. In MatrigelTM model, MCF-DCIS cells grow into multiacinar structures (Fig 
2
bution 
to the periphery of the acini and a more normal steroid acinar structure was observed (Fig 2d).  
In previous xenograft studies at our center, with an Rb-dependent mammary gland dysplasia mouse 
model Tet-op-TAgMMTV-tTA, 10 days of exposure to Palbociclib significantly reduced the percentage of 
hyperplastic and dysplastic ductal structures [58% vs. 7%; p<0.01] and significantly increased the 
percentage of normal-like structures [9% vs. 62%; p<0.01] as compared with untreated controls48. Cyclin 
D1, Cdk6, Cdk4, phospho pRb, DP-1, and E2F-1 were significantly reduced and p21 and p27 significantly 
increased as compared with untreated controls [all p<0.05]. Our preclinical results indicate that 
palbociclib may prevent maintenance of DCIS and its malignant progression.  
Interrupting cancer development by inducing resolution of precancerous lesions is an established cancer 
prevention goal49. Based on preclinical DCIS information and on clinical experience with palbociclib for 
patients with metastatic cancer, the concept of developing palbociclib as potential chemoprevention 
agent is felt to be very promising.  
 
1.3.2 Palbociclib as potential treatment for DCIS 
Nothing is known about the clinical or biological activity of palbociclib in human DCIS or early stage 
breast cancer. This project is designed to understand and describe palbociclib activity in humans, in 
particular in pre-invasive lesions such as DCIS, and to provide critical preliminary data supportive of 
future efficacy studies. For the design of efficacy clinical studies that would lead to potential new label 
indication, preliminary human data must be indicative of its potential clinical usefulness for this 
population of patients. That is the reason for the current study: to generate supportive information in 
humans that will allow the design of a larger efficacy study. 
This study will validate the incorporation of an informative preoperative short treatment phase as 
potential strategy to select DCIS patients, a crucial step for the development of treatment with 
palbociclib in this condition. 
Palbociclib as single agent: The current study will represent a unique opportunity to evaluate the 
potential effect of single agent palbociclib on non-invasive breast lesions. Preclinical models suggest that 
in DCIS, palbociclib single agent may be sufficient. Apart from strong evidence supporting the activity of 
palbociclib combined with endocrine therapy, multiple TNBC cell lines where endocrine therapy would 
have no role have been screened for sensitivity to palbocicilb38,  revealing sensitivity of the luminal-
androgen (LAR) and mesenchymal-stem like (MSL) triple negative subsets. In addition, palbociclib was 
active in the single agent phase IA escalation study A548100152, where 74 heavily pretreated patients 
with various types of solid tumors or lymphomas, including 6 patients with breast cancer, were treated. 
There was 35% SD for at least 2 cycles with one breast cancer patient receiving 50 mg QD with SD lasting 
longer than 10 cycles. Another reason to study single agent palbociclib in DCIS is that endocrine therapy 
is the only systemic treatment currently approved for DCIS. Endocrine therapy has well known potential 
side effects that may interfere significantly with quality of life of patients, including hot flashes, fluid 
retention, vaginal symptoms, thromboembolic complications, cataract, dyslipidemia, arthralgia, 
osteoporosis and uterine cancer 50,51. If palbociclib has biologic activity in DCIS as a single agent, this 
could represent a change in paradigm. 
 

 
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2. OBJECTIVES AND OUTCOME MEASURES 
 
2.1 Hypothesis 
The null hypothesis is that patients with DCIS of the breast who are treated with 12 days of pre-
operative palbociclib will have no change in the gross DCIS pathology, microscopic morphology on 
H&E, or expression of phospho-Rb, Ki-67 proliferation, and multiple other biological markers of their 
cancer. 
 
2.2 Objectives 
 
2.2.1 Primary Objectives 
Feasibility 
Preliminary evidence of DCIS response to palbociclib: Pathologic changes of breast 
tissue comparing paired biopsies before and after treatment (core vs definitive 
surgery) from each patient.  
-
Gross path, H&E changes, multiple biological markers (potentially 
including CDK4 and CDK6 expression, Cyclin D1 expression, P16 
expression, Ki-67 proliferation, TFF1 expression, PCNA expression) 
 
2.2.2 Secondary Objectives 
Toxicities 
Correlative science and tissue banking 
 
2.3 Outcome Measures   
 
Feasibility: the approach will be considered feasible if more than 50% of the enrolled patients are 
treated and followed within protocol rules, if collected samples are suitable for studies, and if pathologic 
changes are detectable when comparing diagnostic and surgical specimens, or treated and untreated 
specimens. In Group A, patients will be treated with palbociclib alone, providing the opportunity to 
address if proposing this kind of treatment for these patients is feasible. Obtaining human data and 
feasibility data would be key for designing efficacy/definitive studies of palbociclib in DCIS. 
Pathology: we will perform descriptive analysis of microscopic and molecular changes upon exposure to 
palbociclib. Biological markers will be tested by immune histochemistry (IHC). Source for comparison will 
be pretreatment versus post-treatment paired samples. This study will represent an opportunity to 
describe potential pathological changes triggered by palbociclib as a single agent in DCIS. 
Toxicity: will be evaluated by CTCAE. There is no plan to compare Groups A and B regarding efficacy or 
toxicity. Toxicity will be descriptive for each treatment group, independently. 
Correlative science: Will be performed at Lombardi Comprehensive Cancer Center. Preliminary data for 
this proposal was obtained using a well-established model of DCIS progression with the human MCF-
DCIS cell line45,47. Proposed translational components are currently routinely done at LCCC. There is no 
plan to compare Groups A and B regarding translational changes. Paired samples (pre- and post-
systemic therapy) will be compared within the respective Group. DCIS Sample #1 is the core biopsy 

 
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done for diagnosis, DCIS Sample #2 is collected at definitive surgery; both collected from the same 
patient (paired).  
 
 
3. STUDY DESIGN 
  
3.1 Description of Study 
   
3.1.1 Overview of Study Design   
 
This is a feasibility study which will evaluate the pre-operative treatment of DCIS of the breast with 
palbociclib. Patients with biopsy-proven DCIS are eligible for the study.  
There will be 2 independent and unrelated study groups of 12 patients each, for a total of 24 patients:  
(a) Group A, of male or female patients treated with palbociclib single agent (n=12);  
(b) Group B, untreated, of male or female patients who consented translational studies in blood, as well 
as diagnostic and definitive surgical specimen, but not the pre-operative treatment with palbociclib 
(n=12).  
 
Figure 3: Study schema  

 
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* Please refer to Timing of Surgery item below for details on scheduling for Group B. 
 
 
Patients will be offered participation in the study at the diagnosis of DCIS (confirmed by pathology). 
Patients could consent biomarker and treatment (Group A) or biomarker-study only (Group B) activities. 
Once the patient is consented, archival tissue from the diagnostic biopsy will be obtained during 
screening and used for research in both Groups A and B. Positive Rb by immunohistochemistry in the 
DCIS component of the lesion will be required for participation on both Groups A and B. Patients 
consenting study participation will be referred to Medical Oncology clinic and undergo screening. After 
successful screening, patients enrolled on Group A will be treated preoperatively with palbociclib. There 
will be no randomization. The assignment to Group A or B 
All patients 
consenting treatment on Group A will receive palbociclib alone. Since some patients may consent tissue 
collection, but not preoperative palbociclib treatment, Group B was created to acquire information 
about contemporary patients receiving biopsy followed by definitive surgery. This approach was first 
described by Stearns and Davidson52. 
Choice of histology: a core biopsy showing DCIS-only will not rule out invasive disease. In some 
instances, invasive disease is found at definitive surgery. Since the proposed treatment will happen 
between diagnostic biopsy and definitive surgery, it is not practical to exclude from analysis patients 

 
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that are found to have invasive disease at definitive surgery that was concomitant with DCIS. 
Information about the invasive component will be collected if present, but the purpose of the current 
project is to describe palbociclib effects on the DCIS component. Likewise, if other concomitant lesions 
are detected at final pathology from definitive surgery, i.e. lobular neoplasia, atypical hyperplasia, 
papilloma, etc, pertinent data will be collected. However, this study will be focused on the effects of 
palbociclib on the DCIS component of lesions. Since hormonal receptors in DCIS are typically available 
only at pathologic specimen from definitive surgery, ER or PR status will not be used for patient 
selection in this feasibility study. Information on ER and PR status will be collected from the pathology 
report of definitive surgery.  
Rb screening: Diagnostic biopsies of participating patients will be tested for Rb expression by 
immunohistochemistry during trial Screening Phase. The expression of Rb in DCIS lesions is expected in 
greater than 80% of the cases53. We estimate 30 patients will need to be screened with Rb staining of 
diagnostic biopsies to complete enrollment. The turnaround time of this test at MedStar Georgetown 
University Hospital when pathology specimen is located at main laboratory is 48-72hr and therefore 
considered feasible as screening procedure. This is based on previous extensive experience at our 
institution with a phase I clinical trial that is ongoing (NCT01522989)54. The population will therefore be 
enriched to increase the likelihood of benefit from this therapy through Rb status evaluation by 
immunohistochemistry (IHC) at study entry. Rb staining will be considered positive when 1+ or above (in 
a scale of 0, 1+, 2+ or 3+).  
Timing of definitive surgery: All enrolled patients will undergo definitive surgery (mastectomy or 
lumpectomy).  
Group A: 
First day of palbociclib treatment will be called Day #1 on study. Last day of palbociclib treatment will be 
called Study Day #12. Definitive surgery will be performed after end of palbociclib in Group A, on Study 
Day #15 +/-1. The short period between end of palbociclib and surgery date was selected observing 
safety and translational data from patients with invasive ductal carcinoma treated with higher dose and 
longer period of palbociclib in the neoadjuvant setting. A long wash out period without the drug prior to 
surgery (2-4 weeks) is not desirable since it may be associated with rebound on Ki67 in patients 
receiving neoadjuvant palbociclib for invasive ductal carcinoma55. In 8 patients receiving additional 
palbociclib 125 mg QD for 12 days until the day prior to surgery, recovery of Ki67 in tissue was 
diminished55. This study also showed that it was safe to proceed with immediate surgery after the 
palbociclib treatment specified above.   
In the current study, the starting date of treatment with Palbociclib for Group A patients will be 
determined by the surgery date schedule. A maximum period of 4 weeks between initial biopsy and 
definitive surgery is estimated for patients enrolled to treatment Group A. In case of cytopenias, surgery 
will be postponed for 7 days (please refer to session 5.1.3 Management of Specific Adverse Events, for 
details). This interval was felt to be acceptable and in line with current practice out of clinical trials. 
Minimum length of time from enrollment to definitive surgery on treatment Group A is estimated 18 
days (Eligibility verification, Rb-testing, Palbociclib dispensation, Palbociclib treatment for 12 days and 
definitive surgery after stopping treatment). 
Group B: 
There is no preoperative palbociclib treatment in Group B. Accounting for healing process after 
diagnostic biopsy, consenting process, Rb screening and to prevent excessive delays since original 
diagnosis, we recommend that definitive surgery occurs between 5 and 42 days since original diagnostic 
biopsy.  

 
Protocol WI223281  Palbociclib in DCIS  Mainor 
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Collection of tissue at definitive surgery (sample #2): A certified pathologist will be responsible for tissue 
handling and destination to research. Unfortunately, performing a research-only core at surgery is not 
felt to be practical in patients with diagnosis of DCIS, since one of the key components of pathologic 
exam is to rule out invasive component. Therefore, an additional core at surgery is not felt to be safe for 
patients. Tissue will be collected for translational studies based on certified pathologist examination of 
material and without compromise of definitive diagnosis. There is a possibility that at definitive surgery 
invasive lesions are detected. We will describe the same parameters for DCIS lesions and for invasive 
lesions. Invasive component histologic abnormalities description will be purely exploratory. The focus of 
this study is DCIS. Pathologist will fill out a form confirming collection of sample for the trial (Appendix L) 
 
Follow up period: Patients will be followed at the postoperative period in the outpatient setting, at 
which point any additional systemic treatment for DCIS or invasive breast cancer will be discussed. The 
End of Study visit will occur approximately 2 to 3 weeks after surgery. The Informed Consent form will 
contain terminology asking patients for permission for the researchers to review the medical chart at 1 
year and at 5 years from enrollment to collect additional clinical information about medical history, 
disease status and treatments.  
The study procedures are summarized in Appendix A.  
The study schema is presented in Appendix B.  
The calendar template for treatment and visits timeline planning based on surgery date for patients 
enrolled on treatment Group A (Palbociclib) is presented in Appendix C.  
The Enrollment Process to Treatment Overview is presented in Appendix D. 
 
3.2 End of Treatment 
The total duration of Palbociclib treatment is 12 days, beginning any time after enrollment. Definitive 
surgery will occur 3 (+/- 1day) after end of palbociclib treatment, on study day #15 +/- 1 day. The end of 
treatment visit will occur 32 (+/- 8 days) after surgery. Unless a patient discontinues treatment early or 
experiences treatment delays, this would result in 24-40 days on trial. Any premature, permanent 
-
 
Any one of the following criteria will be reason to stop IP-treatment before 12 days: 
General or specific changes in the participant's condition render the participant not a candidate 
for further treatment in the opinion of the treating investigator  
Unacceptable toxicity or unacceptable adherence to palbociclib.  
Patient withdraws consent 
 
3.3 End of Study 
The study ends when all enrolled patients complete trial procedures.  
End of study is the date when the last patient has completed their end of study visit, all data have been 
collected, and all queries have been resolved. 
 

 
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4.6.2 Study 
Termination  
2.3 Outcome Measures; feasibility
 
 
3.3.1 End of Study Visit 
study visit is the last formal study visit, or last formal contact or an unscheduled study 
visit in case of early withdrawal from all Phases of the study for treatment and follow-up.  
 
3.3.2 Managing Patients Who Never Received Protocol Treatment 
Patients who never received definitive surgery will be substituted. 
Patients who are enrolled to the trial on Group A, but never received Palbociclib will be substituted. 
 
3.3.3 Patients Lost to Follow Up 
During the duration of the study, sites will be expected to continue efforts to contact all enrolled 
patients as well as regularly consult publicly available information to ascertain vital status of the patient. 
After End of study visit, patients will allow long term follow up through medical records review for 
medical history, additional treatments, disease and survival status, as well as a telephone call at 1yr and 
at 5yrs from definitive surgery. In cases where sites cannot successfully contact a patient and is not able 
to receive appropriate publicly available information for greater than two years, the patient will be 
noted as lost to follow up. 
     
3.4 Rationale for Study Design  
 
3.4.1 Rationale for Test Product Dosage (Palbociclib) 
 
Choice of palbociclib dose: A smaller than approved dose was selected for safety concerns, minimizing 
the risk of neutropenia in the pre-operative period. We expect this dose to be efficacious against the 
early stage lesions from enrolled patients based on described experience in palbociclib study 
A548100142. In that single agent escalation study plasma pharmacokinetics parameters had low 
variability with a small dose-dependent increase in exposure over the dose range of 100 to 150 mg, 
based on Cmax and AUC from 0 to 10 hours. The dose limiting toxicity was neutropenia. During cycle #1 
the more severe neutropenia reported at 100mg daily was graded as 2 (CTCAE). With 125mg daily, 
neutropenia reached grade 3.  
 
A) Group A (Palbociclib treatment)   
Group A will receive palbociclib 100mg by mouth daily for 12 days prior to definitive surgery. 
Palbociclib will be provided by Pfizer. 
B)  Group B (Observation)  
Group B will receive no preoperative treatment.  
 

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4.2.1 Study Site
This study will be open at the MedStar Georgetown University Hospital/Lombardi Comprehensive 
Cancer Center (LCCC) and Medstar Washington Hospital Center. 
4.2.2 Study Coordinators and Pharmacists
There will be a study coordinator overseeing the study. Lombardi Research Pharmacy will be responsible 
for dispensing Palbociclib according to Institutional SOPs for experimental treatments for oral use. 
4.2.3 Patient Enrollment
Figure 4: Patient enrollment procedures:
Please refer to the procedures below for details on patient enrollment.
1.
Study coordinator or treating physician screens patient for eligibility criteria.
a.
If patient does not meet eligibility criteria, stop and report screen failure and/or reason.
2.
If patient meets initial eligibility screening, patient can sign informed consent and HIPAA 
authorization form. Consent can be obtained by study coordinator or treating physician.
3.
Study coordinator or treating physician completes Eligibility Checklist in Appendix E. 

 
Protocol WI223281  Palbociclib in DCIS  Mainor 
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c)
Pathology report stating Rb status positive 
d)
Tentative date for definitive surgery (Lumpectomy, Mastectomy, etc) 
e)
Clinic notes containing information on ECOG PS, previous and current treatments, co-
morbidities, and information pertaining to eligibility for the trial 
f)
Current negative beta HCG test report (blood or urine) for women of childbearing potential 
 Group A only 
g)
Current Complete Blood Count with differential and Platelets  Group A only 
h)
Current Bilirubin levels and normal range at local laboratory  Group A only 
i)
Current Creatinine levels and normal range at local laboratory  Group A only 
j)
Current AST levels and normal range at local laboratory  Group A only 
k)
Current ALT levels and normal range at local laboratory  Group A only 
 
 
The informed consent form 
addition to keeping the physical document signed by the patient and treating physician in the study 
binders, as per standard operating practice. 
 
All participants must be registered and enrolled through the Oncology Research office at MedStar 
Georgetown University Hospital. 
 
 
4.3 Study Treatment  
Palbociclib will be provided by Pfizer. Patients enrolled on Group A will receive Palbociclib. 
 
4.3.1 Formulation, Packaging, and Handling 
 
4.3.1.1 Formulation of Palbociclib  
Palbociclib capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase 
inhibitor. The molecular formula for palbociclib is C H N O . The molecular weight is 447.54 daltons. The 
chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl) pyridin-2-yl]amino]-pyrido[2,3-
d]pyrimidin-7(8H)-one. In this study, 100 mg capsules will be used. Those are 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. 
 
4.3.1.2 Labeling of Palbociclib  
Palbociclib Drug Substance and Drug Product are manufactured, labelled and packed according to 
current Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines for use in the 
clinical studies. Each lot of palbociclib for clinical studies is subjected to a series of quality control tests 
to confirm its identity, purity, potency, and quality. 
 

 
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4.3.1.3 Acquisition and Storage of Palbociclib 
Palbociclib is an FDA approved drug, dispensed in bottles of 21 capsules of palbociclib 100mg (NDC 
0069-0188-21). Palbociclib will be provided without charge to the patients or MedStar Georgetown 
University Hospital by Pfizer and given to the patients on Group A treatment arm. Pfizer will ship 
Palbociclib to study center, where it will be stored until dispensed. Appendix H shows the Drug Supply 
Request Form to be used by the pharmacist to request medication from Pfizer. Shipment of Palbociclib 
from Pfizer to the study site will be coordinated by a dedicated pharmacist. Palbociclib will be stored in 
the pharmacy until needed, as per standard operating procedures.  
Palbociclib will be stored at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C 
(59 °F to 86 °F). Further storage and stability conditions are stated in the palbociclib IB. 
Investigator and site staff are requested to check storage temperatures daily (i.e. manually or by using 
alarm systems to alert of any excursions) and ensure that thermometers are working correctly as 
required for proper storage of investigational products. 
Deviations from the storage requirements, including any actions taken, must be documented and 
reported to the respective study Sponsor PI. Once a deviation is identified, palbociclib must be 
quarantined and not used until receipt of documentation of permission to use the investigational 
product. 
Medication should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Medication which has been returned by the patients should be stored 
separately from medication that needs to be dispensed. 
 
4.3.1.4 Dispensation of Palbociclib  
The dedicated pharmacist at each site will also be responsible for dispensing the drug to the treatment 
group patients, as per standard operating practices. Investigator will fill out the Investigational Drug 
Order Form (Appendix I) ordering Palbociclib for a patient. The coordinator will present the filled order 
form to the Pharmacist so that Palbociclib can be dispensed. 
Study pharmacist will dispense 12 capsules for each participant enrolled to Cohort A (treatment cohort). 
The patient number should be recorded on the bottle label in the spaces provided by site personnel at 
the time of assignment to patient. Site personnel must ensure that patients clearly understand the 
directions for self-medication. Patients should be given a sufficient supply to last until their next study 
visit and should further be instructed to keep their medication in the bottles provided and not transfer it 
to any other container. No other medicines should be added to palbociclib bottle. 
Due to possible unknown hazards associated with topical and environmental exposure to experimental 
agents, capsules must not be opened and/or emptied into any vehicle for oral ingestion; capsules must 
be swallowed intact. 
To ensure adequate records and patient compliance monitoring, palbociclib capsules will be accounted 
for by the site as instructed by the respective study Sponsor and following MGUH standard operational 
procedures. Hence, the study site pharmacy will maintain a careful record of the inventory and 
disposition of the agent. Accurate records of all investigational product received at, dispensed to, 
returned from, returned to, and disposed of by the study site should be recorded. Patients will be 
instructed to return previously dispensed bottles (including unused drug and/or empty bottles) as well 
as their completed Palbociclib Diary to the clinic at the pre-operative visit for accountability purposes 

 
Protocol WI223281  Palbociclib in DCIS  Mainor 
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(Appendix J). Unused returned medication MUST NOT be re-dispensed to patients. The number of 
remaining capsules/tablets will be documented and recorded within the eCRF.  
 
4.3.1.5 Palbociclib destruction or return 
Sites will have to destroy or return unused Palbociclib. The site's principal investigator must ensure that 
any materials are destroyed or returned in compliance with applicable environmental local regulations, 
institutional policy, and any special instructions provided by Pfizer, Inc. Verification of drug 
accountability has to be completed before any IP is destroyed at site. Destruction or return of 
investigational product must be adequately documented. 
 
 
 
4.3.2 Dosage, Administration, and Compliance  
 
4.3.2.1 Group A 
Patients enrolled to Group A will receive a 12-day course of Palbociclib before surgery. They will receive 
Palbociclib 100mg PO daily x 12 days. When definitive surgery date is defined and Operation Room 
scheduled, day 1 of palbociclib will be determined and Palbociclib dispensed. Administration is 
performed on an outpatient, self-administration basis. Appendix C has a model calendar that can be 
used when planning events based on defined date of surgery.  
 
Treatment is continuous daily for 12 days, followed by 3 days off [+/- 1 day], followed by 
definitive DCIS surgery. 
Patients will be encouraged to take their dose of Palbociclib at approximately the same time 
each day.  
Palbociclib should be taken with food.  
If the patient vomits or misses a dose, an additional dose should not be taken. The next 
prescribed dose should be taken at the usual time.  
Palbociclib 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 who inadvertently take 1 extr
 
If patient takes more than two doses of palbociclib in a day, the patient should bring this to the 
attention of his or her treating physician. 
Patients should be instructed to record daily administration of the study drug in the Palbociclib 
Diary (Appendix J). 
  
 

 
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4.3.2.2 Group B  
These patients will receive no pre-operative treatment. Core biopsies from diagnosis and material from 
definitive surgery will be collected for translational studies and tissue banking. They will also provide 
blood samples at screening and prior to definitive surgery. Please refer to item 3.1.1 Overview of Study 
Design, timing of surgery, for additional details on definitive surgery timing after enrollment for patients 
on Group B (no palbociclib).    
 
4.3.2.3 Assessment of Compliance with Palbociclib  
Study coordinator will meet with patient before surgery and after end of palbociclib treatment and 
collect empty bottles. At that point the coordinator will document compliance to treatment per 
protocol. 
 
4.3.2.4 Other Required Medication 
No other treatment will be required per protocol. 
 
 
4.4 Concomitant Therapy 
All prior treatment or medication administered during the 30 days prior to enrollment and any 
concomitant therapy administered to the patient throughout the study until date of surgery must be 
recorded on the respective page of the eCRF. The generic or trade name of the drug must be specified 
along with the dose, the duration of treatment, relation to AE and indication for use. 
 
4.4.1 Surgery 
Definitive surgery for DCIS treatment is permitted and should occur during participation on the trial.  
If any other major surgery is urgently required, the patient will come off study and palbociclib 
discontinued. 
 
4.4.2 Radiotherapy 
Radiation therapy is not allowed before recovery from definitive surgery, or during participation on the 
trial. If radiation therapy is urgently required, the patient will come off study and palbociclib 
discontinued. 
 
4.4.3 Hormone Therapy 
Hormone therapy is not allowed during the trial. Patients receiving hormone therapy for previous 
diagnosis of DCIS or invasive cancer should discontinue this therapy at least 4 weeks prior to undergoing 
pre-treatment biopsy.  
Hormone replacement therapies are allowed except for estrogen, progesterone, GnRH agonists and 
antagonists. Examples of allowed hormone therapies are insulin are levothyroxine. 
 

 
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4.4.4 Permitted Therapy  
Supportive care medications are allowed at any time on trial, as long as they are not included in the list 
of prohibited medications based on CYP induction (Section 4.4.5). 
 
4.4.5 Prohibited Therapy 
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, 
palbociclib is a time-dependent inhibitor of CYP3A. Use of the following concomitant therapies will not 
be permitted during the study: 
 
Strong CYP3A inhibitors 
Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib 
in healthy subjects by 87%. Examples of strong CYP3A inhibitors are clarithromycin, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, and voriconazole. Grapefruit or grapefruit juice should also be 
avoided during Palbociclib treatment. 
 
Strong CYP3A inducers 
Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of Palbociclib in 
healthy subjects by 85%. Examples of strong CYP3A inducers are phenytoin, rifampin, carbamazepine, 
enzalutamide, and St John's Wort. 
 
Drugs That May Have Their Plasma Concentrations Altered by Palbociclib 
Co-administration of midazolam with multiple doses of Palbociclib increased the midazolam plasma 
exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The following 
sensitive CYP3A substrates with a narrow therapeutic index will not be allowed during participation on 
the study: alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, 
quinidine, sirolimus and tacrolimus. 
 
Gastric pH Elevating Medications 
In a drug interaction trial in healthy subjects, co-administration of a single 125 mg dose of Palbociclib 
with multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed conditions had limited 
impact on AUC (13% decrease), when compared to a single dose of Palbociclib administered alone. 
Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, 
the effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is 
expected to be minimal. Under fed conditions there is no clinically relevant effect of PPIs, H2- receptor 
antagonists, or local antacids on palbociclib exposure. 
 
 
4.5 Study Assessments  
 

 
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The study consists of 6 different phases: 
1)
Pre-Screening Phase 
(candidates for study either on Group A or Group B) 
2)
Screening Phase  
(Group A and Group B)  
Study Days -28 to 0 
3)
Treatment Phase  
(Group A only)*  
 
Study Days 1 to 12 
4)
Pre-Surgery Phase 
(Group A only)*  
 
Study Days 12 to 14 
5)
Surgery  
 
(Group A and Group B)* 
Study Days 14 to 16 
6)
Follow-Up Phase - EOV  (Group A and Group B)  
Study Days 25 to 40 
Follow-Up Phase - LTF  (Group A and Group B)  
EMR review 1yr and 5yr  
 
* Please refer to item 3.1.1 Overview of Study Design, timing of surgery, for additional details on definitive surgery timing after 
enrollment for patients on Group B 
 
See Appendix A Study Procedures and Appendix B Study Schema for details as to how these phases 
correspond with the Schedule of Assessments calendar, Pre-Screening Phase, Screening Phase, 
Treatment Phase, Pre-Surgery Phase, Surgery and Follow-Up Phases End of Study Visit (EOV) and Long 
Term Follow Up (LTF). 
 
4.5.1 Pre-Screening phase 
Pre-Screening Phase is when the patient receives the diagnosis of DCIS based on pathology from a 
diagnostic procedure and is felt to be a candidate for the study. During this phase imaging studies are 
reviewed and case discussed among providers/investigators. On occasional circumstances DCIS may be 
suspected based on imaging, and yet to be confirmed by pathology diagnosis. In this case a biopsy 
should take place establishing the diagnosis of DCIS prior to confirming patient eligibility for the study.  
 
4.5.2 Screening phase 
The Screening Phase is the time between the date a patient provides written informed consent, and the 
time the patient completes enrollment procedures/has enrollment verified by the Lombardi Project 
Manager (PM). Data collection and procedures during this time period include patient demographics, 
eligibility requirements, concomitant medications, medical history, physical examination/vital signs, 
ECOG performance status assessment, baseline symptoms/adverse events, severe adverse events, 
laboratory measurements, pregnancy testing (if applicable), biospecimens (blood and tissue sample #1), 
and Rb testing. During the Screening Phase, only AEs deemed to be serious (SAEs) and related to 
protocol mandated and not routinely performed procedures have to be reported.  
 
4.5.2.1 Pathologic diagnosis of DCIS - Biopsy 
This procedure must be completed before registration by LCCC PM to trial. Typically, patient will be 
offered the trial after pathologic diagnosis of DCIS. However, the trial may be offered to patients prior to 
diagnostic biopsy, in case of highly suggestive radiological findings for DCIS. In this case, patients will 
need to complete diagnostic biopsy for eligibility. Fine needle aspiration is not acceptable. Patient can 

 
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undergo core biopsy, stereotactic biopsy or incisional biopsy of breast lesion, as long as the lesion is not 
completely resected during the procedure.  
 
4.5.2.2 Rb Screening for Eligibility and Central Assessment of Hormone Receptor Status 
All patients enrolled on this study will have baseline DCIS samples (Tissue sample #1) tested for Rb 
status at a CLIA-certified lab (for instance, MGUH Pathology Department) prior to registration. Rb 
staining will be done by immunohistochemistry and considered positive when 1+ or above (in a scale of 
0, 1+, 2+ or 3+). Rb testing negative at screening is criterion for screen failure. 
  
4.5.2.3 Medical History and Demographic Data  
Demographic data will include age, sex, and self-reported race/ethnicity. 
Medical history includes clinically significant diseases that are currently active or that were active, 
including major surgeries, within the previous 5 years, any cancer history (including prior cancer 
therapies and procedures) and reproductive status.  
 
Patients may be considered postmenopausal in case that one of the following criteria applies: 
prior bilateral oophorectomy, OR 
, OR 
chemotherapy and/or endocrine therapy exposure, OR 
Age < 60 years hysterectomized and FSH and plasma estradiol levels in the post-menopausal 
range according to local policies prior to chemotherapy and/or endocrine therapy exposure 
 
If none of the above mentioned criteria fully applies, the patient may be judged premenopausal 
according to local policies. In the absence of procedure that prevents fertility (such as tubal ligation, 
hysterectomy, vasectomy) premenopausal patients must be tested negative for pregnancy prior to 
enrollment on Group A (Palbociclib treatment).  
 
4.5.2.4 Physical Examinations and Vital Signs 
At screening, a physical examination including a palpation of breast/chest wall, axillae, supra- and 
infraclavicular region, height, weight, blood pressure and pulse rate is required. Symptom-directed 
physical examinations, blood pressure, weight and pulse rate will be performed. All physical 
examinations and vital signs assessments should be performed by a physician or registered nurse or 
other qualified health care provider according to local regulations. 
 
4.5.2.5 Radiology 
All available radiology studies will be reviewed before treatment start. Questions may be discussed 
directly with radiologist, as well as at the weekly Lombardi Multidisciplinary Breast Cancer Meeting. 
 

 
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4.5.2.6 Laboratory Assessments  
It is ideal that laboratory assessments be performed at the research center, since blood will also be 
collected for biorepository. During the Screening Phase, all laboratory assessments must be performed 
within 28 days of treatment start in Group A. In Group B, screening blood samples should be drawn at 
least 5 days prior to surgery date. 
 
Hematology: 
Hemoglobin, white blood cell (WBC) count, absolute neutrophils and platelet count. 
 
Blood chemistry with liver function tests: 
AST/ALT, alkaline phosphatase, sodium, potassium, CO2, chloride, total calcium, total bilirubin, 
serum creatinine, BUN, total protein and albumin. 
 
Serum/urine pregnancy test, if required 
 
4.5.2.7 Mandatory Blood Samples for Biomarker Analysis 
 
During screening phase blood samples will also be collected for storage at the Lombardi Biorepository. 
These are research samples.  
 
Group A: In Group A there will be 3 time points for research blood collection.  
1.
The first research blood samples will be collected after consenting and prior to palbociclib 
treatment.  
2.
The second research blood sample will be collected after end of palbociclib and prior to surgery, 
typically on the date of surgery.  
3.
The third research blood sample will be collected after surgery (End of treatment visit). 
 
Group B: In Group B there will be 2 time points for research blood collection.  
1.
The pre-operative research blood sample can be collected any time after consenting and prior to 
surgery in Group B.  
2.
The second research blood sample will be collected after surgery (End of treatment visit). 
 
Appendix M contains the Research Blood Sample Form, to be filled on the day of sample collection and 
handling until its storage. Samples from this project will be stored at the Riegel Lab.  
 
 
4.5.3 Treatment phase 
During this phase, patients enrolled to treatment Group A will receive IP treatment (palbociclib). 
Treatment Phase for patients on Group A can start as soon as patient successfully completes screening 
and has the definitive date for surgery determined by the surgeon. Palbociclib starting date will be 

 
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defined by date of definitive surgery. The time period for this phase will be 14 to 16 days. This period 
starts on the date of dose #1 of Palbociclib. Palbociclib treatment is to be given for 12 days.  
Patients enrolled to Group B will receive no treatment prior to surgery. 
 
4.5.4 Pre-Surgery phase  
For patients enrolled to Group A, on Day 13 +/-1 there will be a pre-operative clinic visit, when tolerance 
to therapy will be assessed, including physical examination/vital signs, ECOG performance status 
assessment, adverse events, serious adverse events, IP accountability, concomitant medications, 
measurements of treatment adherence. Laboratory tests will include CBC, CMP and an additional blood 
sample for research (please refer to item 4.5.2.7 Mandatory Blood Samples for Biomarker Analysis). 
After this visit, patients will proceed to scheduled definitive surgery for DCIS. Treatment phase ends on 
the day of surgery (Day 15 +/-1). 
For patients enrolled to Group B the pre-surgery experimental phase will only involve Laboratory tests 
including CBC, CMP and an additional blood sample for research (please refer to item 4.5.2.7 Mandatory 
Blood Samples for Biomarker Analysis). 
 
4.5.5 Surgery 
registration, OR procedures and subsequent discharge home. Surgery will occur on study day 15 +/-1. 
Research tumor sample will be collected under the supervision of certified pathologist (Tumor Sample 
#2). The research tumor sample will be transported to Riegel Lab where it will be processed and stored 
for testing. The surgery must happen at the study participating center. 
 
4.5.6 Follow up phases  End of Study Visit and Long Term Follow Up 
Follow-Up Phase starts on post operative day #1. The End of Study Visit (EOV) occurs on treatment day 
32 +/- 8, which represents a time point situated approximately at 2 to 3 weeks after surgery. On that 
date, there will be a clinic visit with physical examination/vital signs, ECOG performance status 
assessment, adverse events, serious adverse events, current medications, and final pathology report. 
Additional treatments may be required after definitive surgery. Patient will discuss any additional 
treatments with the primary or treating medical oncologist. Laboratory tests will include CBC, CMP and 
an additional blood sample for research. A Long Term Follow up (LTF) assessment may be done at year 1 
(+/- 30 days) and at year 5 (+/- 60 days) from treatment. The LTF assessment may comprise of Electronic 
Medical Record Review for clinical data and survival status as well as of a telephone call.  
 
 
4.6 Patient and Study Discontinuation 
Patients who are non-compliant or discontinue Study Treatment will be substituted. Withdrawal of 
consent for all study participation will end patient activity in the study, translational research and clinical 
follow up. 

 
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5. ASSESSMENT OF SAFETY  
 
5.1 Safety Plan  
Palbociclib is currently approved in the US for metastatic breast cancer and is currently in clinical 
development on other indications. The toxicity is considered predicable based on significant experience 
with palbociclib on phase I, II and III clinical trials, expanded access, and standard of care use. 
 
5.1.1 Dose Delays and Modifications for Palbociclib 
Palbociclib will be used at a lower dose of 100mg PO daily for 12 consecutive days. There will be no dose 
delays or dose reductions in this trial.  
Every effort should be made to administer study treatment on the planned dose and schedule. 
However, in the event of significant treatment-related toxicity, administration of palbociclib will be 
discontinued. Patients who discontinue study treatment (i.e. palbociclib for Group A) will continue to be 
followed according to post treatment follow up as defined in Schedule of Study Procedures (Appendix 
A). 
 
5.1.2 Treatment discontinuation 
Incidence, nature, and severity of adverse events triggering study treatment discontinuation are to be 
assessed by the investigator and graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0), with respective attribution. 
Any grade 3 or higher toxicity will trigger treatment discontinuation. In case of concurrent occurrence of 
> 3x ULN ALT and 2x ULN Total Bilirubin, at any time during the trial, palbociclib will be permanently 
discontinued. 
 
5.1.3
Management of Specific Adverse Events  
 
5.1.3.1 Neutropenia 
3 is required at baseline for study participation. Patients 
enrolled on treatment Group A will have a pre-surgery visit at day 13 +/-1 for clinical and laboratorial 
evaluation. Surgery will be scheduled to occur on day 15 +/- 1. If pre-operative counts reveal 
neutropenia, the definitive surgery will be postponed until recovery of neutrophil counts.  
 
5.1.3.2 Thrombocytopenia 
20,000/mm3 are required at baseline for study participation. Patients enrolled on treatment 
Group A will have a pre-surgery visit at day 13 +/-1 for clinical and laboratorial evaluation. Surgery will 
be scheduled to occur on day 15 +/- 1. If pre-operative counts reveal platelets lower than 80,000/mm3, 
the definitive surgery will be postponed until recovery of platelet counts. 

 
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5.1.4 Pregnancy and Contraception Use 
Pregnancy is contraindicated during Palbociclib therapy and for at least 3 weeks after the last dose. 
Based on findings from animal studies and its mechanism of action, Palbociclib can cause fetal harm 
when administered to a pregnant woman. There are no available data in pregnant women to inform the 
drug-associated risk. In animal reproduction studies, administration of palbociclib to pregnant rats and 
rabbits during organogenesis resulted in 
the human clinical exposure based on AUC. Patients will be advised regarding the potential risk of 
Palbociclib exposure to a fetus. The estimated background risk of major birth defects and miscarriage for 
the indicated population is unknown. In the U.S. general population, the estimated background risk of 
major birth defects and miscarriage in clinically recognized pregnancies is 2 4% and 15 20%, 
respectively. 
 
5.1.4.1 Adequate Non-Hormonal Contraception  
Adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization) 
OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel 
/ film / cream / suppository). 
 
5.1.4.2 Timing and Duration of Contraception  
Females 
Palbociclib can cause fetal harm when administered to a pregnant woman. Females of reproductive 
potential will be advised to use effective contraception during treatment with Palbociclib and for at least 
3 weeks after the last dose. 
Males 
Because of the potential for genotoxicity, male patients with female partners of reproductive potential 
will be advised to use effective contraception during treatment with Palbociclib and for 3 months after 
the last dose. 
 
 
5.1.5 Lactation 
There is no information regarding the presence of palbociclib in human milk, nor its effects on milk 
production or the breastfed infant. Because of the potential for serious adverse reactions in breastfed 
infants from Palbociclib, advise a lactating woman not to breastfeed during treatment with Palbociclib 
and for 3 weeks after the last dose. 
 
5.1.6 Geriatric Use 
Geriatric participation is allowed in this study. Of 84 patients who received Palbociclib in a study, 37 
 

 
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received Palbociclib in Study 2, 86 
or effectiveness of Palbociclib were observed between these patients and younger patients.  
 
 
5.2 Safety Parameters and Definitions 
 
5.2.1 Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of 
causal attribution. An adverse event can therefore be any of the following: 
 
a. Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product 
b. Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, 
or severity of a known condition). 
c. Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
d. Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is associated 
with symptoms requires additional diagnostic testing or medical/surgical intervention, leads to a 
change in study treatment or concomitant treatment or discontinuation from study drug or is 
considered to be an AE by the Investigator. 
e. Adverse events that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment. 
 
The investigator is responsible for ensuring that all adverse events (as defined above) are recorded on 
the respective Adverse Event eCRF page and additionally reported to the IRB in case the AE fulfills the 
criteria for expedited reporting. 
 
For each adverse event recorded on an Adverse Event eCRF page, the investigator will make an 
assessment of seriousness, severity, and causality. The prompt reporting of adverse events is the 
responsibility of each investigator engaged in clinical research, as required by applicable regulations. 
Adverse events must be described and graded using the terminology and grading categories as defined 
 
 
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE. To assist in the 
determination of case seriousness further information may be requested from the investigator to 
provide clarity and understanding of the event in the context of the clinical study. 
 
 

 
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5.2.2 Serious Adverse Events (Immediately Reportable to the Sponsor) 
For this protocol, serious adverse events (SAEs) are defined as follows: 
It results in death (i.e., the AE actually causes or leads to death). 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at immediate 
risk of death. It does not include an AE that, had it occurred in a more severe form, might have 
caused death.). 
It requires or prolongs inpatient hospitalization.  
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
Palbociclib. 
It is considered a significant medical event by the investigator based on medical judgment (e.g., 
may jeopardize the subject or may require medical/surgical intervention to prevent one of the 
outcomes listed above). 
 
5.2.3 Non-Serious Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
This study will not have adverse events of special interest (AESI) for reporting. 
There are no protocol-specified SAEs in this study. 
 
5.2.4 Medication errors 
Medication errors may result from the administration or consumption of the wrong drug, by the wrong 
patient, at the wrong time, or at the wrong dosage strength. Such medication errors occurring to a study 
participant are to be captured on the medication error CRF which is a specific version of the adverse 
event (AE) page, and on the SAE form when appropriate. In the event of medication dosing error, the 
Sponsor PI should be notified immediately (within 24hr from learning about the event). 
 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, including: 
- Medication errors involving patient exposure to the investigational product 
- Potential medication errors or uses outside of what is foreseen in the protocol that do or do not 
involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, the 
medication error should be captured on the medication error version of the adverse event (AE) page 
and, if applicable, any associated adverse event(s) are captured on an adverse event (AE) CRF page. 
 
 
5.3 Methods and Timing for Capturing and Assessing Safety Parameters 
 

 
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5.3.1 Adverse Event Reporting Period  
Adverse event (Safety) reporting is mandatory from the date of informed consent form signature (i.e., 
screening phase) until the last visit of the treatment phase, 26 to 32 days after surgery. During the 
Screening Phase, only AEs deemed to be serious (SAEs) and related to protocol mandated and to non-
routinely performed procedures have to be reported. 
 
5.3.2 Eliciting Adverse Event Information  
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the patient. 
In addition, each study patient will be questioned about AEs. 
 
5.3.3 Assessment of Adverse Event Severity  
The adverse event severity grading scale for the NCI CTCAE (v 4.0) will be used for assessing adverse 
event severity. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A 
copy 
of 
the 
CTCAE 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. The grading system 
below will be used for assessing severity for adverse events that are not specifically listed in the NCI 
CTCAE. 
 
Grade
Severity
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-
appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
 
Legends: 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, feeding 
one's self, using the toilet, and taking medications, as performed by patients who are not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious adverse 
event,  

 
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d Grade 4 (only if immediately life threatening) and 5 events must be reported as serious adverse 
events 
 
5.3.4 Assessment of Causality of Adverse Events  
Investigators should use their knowledge of the patient, the circumstances surrounding the adverse 
event, and an evaluation of any potential alternative causes to determine whether or not an adverse 
event is considered to be related to the IP or Non-IP, indicating "yes" or "no" accordingly. The following 
guidance should be taken into consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
Course of the event, considering especially the effects of dose reduction, discontinuation of 
study drug, or reintroduction of study drug (where applicable) 
Known association of the event with the study drug or with similar treatments 
Known association of the event with the disease under study 
Presence of risk factors in the patient or use of concomitant medications known to increase the 
occurrence of the event 
Presence of non-treatment-related factors that are known to be associated with the occurrence 
of the event 
 
Adverse Event Attribution Categories:  
 
Definitely 
Direct association with study agent; clearly related 
Probably 
More likely explained by study agent 
Possibly 
Study agent and other cause explained equally well; maybe related 
Probably 
Not 
More likely explained by other cause; doubtfully related to the 
intervention 
Unrelated 
Clearly explained by other cause; clearly NOT related to the intervention 
 
 
5.3.5 Procedures for Recording Adverse Events 
 
5.3.5.1 Abnormal Laboratory Values  
The criteria for determining whether an abnormal objective test finding should be reported as an AE are 
as follows: 
- Test result is associated with accompanying symptoms; and/or 
- Test result requires additional diagnostic testing or medical/surgical intervention; and/or 

 
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- Test result leads to a change in study dosing, or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy; and/or 
- Test result is considered to be an AE by the investigator or Sponsor 
- Test causes delay of definitive surgery. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
 
 
5.4 Immediate Reporting Requirements  
 
5.4.1 Emergency Medical Contacts  
Participating investigators must report each serious adverse event to the Sponsor within 24 business 
hours of learning of the occurrence. In the event that the participating investigator does not become 
aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within business hours after learning of it and document 
the time of his or her first awareness of the adverse event. Report serious adverse events by telephone, 
email or facsimile to: 
 
 
 
The subject line of an email should clearly state that this is an urgent message regarding SAE on this 
study. 
 
 
5.4.2 Serious Adverse Events Reporting Requirements  
 
5.4.2.1 Reporting of Serious Adverse Events 
When learning about and SEA (SAEs definition section 5.2.2), the Sponsor PI or their designee will notify: 
1.
The IRB and DSMC by a written safety report within one (1) business day of learning of the SAE; 
2.
Pfizer by facsimile within seven (7) calendar days of the first awareness of the event 
(immediately if the event is fatal or life-threatening), if:  
Study subjects who are assigned to receive the Pfizer Product Palbociclib; or  
Individuals otherwise exposed to the Pfizer Product as described below.  
The Sponsor PI will provide additional details about the SAE to the IRB and DSMC, as well as Pfizer as it 
becomes available. Sponsor Principal Investigator should report SAEs as soon as they are determined to 

 
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meet the definition, even if complete information is not yet available. Within the following 1-2 business 
days of awareness, the participating investigator must provide follow-up information on the serious 
adverse event if a full description of events was not included with the initial reporting of the event to 
Sponsor PI. Follow-up information should describe whether the event has resolved or continues, if and 
how the event was treated, and whether the participant will continue or discontinue study participation. 
Sub-investigators should submit this information to the Sponsor PI at 
.  
Additional information that should be reported as SAEs include data related to overdose, abuse, off-
label use, misuse, inadvertent/erroneous administration, medication error or occupational exposure, 
with or without association with an AE/SAE unless otherwise specified in the protocol.  
All non-serious adverse events will be reported to the Sponsor on the adverse events CRFs. 
As used in this Agreement, the term SAE will be understood to include exposure during pregnancy, 
exposure during lactation, and occupational exposure (refer to section 5.4.2.2). 
 
5.4.2.2 Exposure during Pregnancy, Exposure during Lactation, Occupational Exposure 
Even though there may not be an associated SAE, exposure to the Pfizer Product Palbociclib during 
pregnancy, during lactation, and occupational exposure are reportable.  Abortions and congenital 
anomalies should also be reported. 
 
 
Cases of potential drug-
also reportable to Pfizer. If a Study subject develops abnormal values in aspartate transaminase (AST) or 
alanine transaminase or both, concurrent with abnormal elevations in total bilirubin and no other 
known cause of liver injury, that event would be classified a
 
 
5.4.2.4 SAE Reporting Period 
The SAEs that are subject to this reporting provision are those that occur from after the first dose of 
Palbociclib through 28 calendar days after the last administration of the Pfizer Product. In addition, if 
Principal Investigator becomes aware of an SAE occurring any time after the administration of the last 
dose of the Palbociclib, Sponsor PI should report that SAE to Pfizer if a causal relationship between the 
Pfizer Product and the SAE is suspected.  
 
5.4.2.5 Follow-Up Information 
Principal Investigator will assist Pfizer in investigating any SAE and will provide any follow-up 
information reasonably requested by Pfizer. 
 
5.4.2.6 Regulatory Reporting 
Reporting an SAE to Pfizer does not relieve Principal Investigator of responsibility for reporting it to 
appropriate regulatory authorities, if such reporting is required. 

 
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5.4.2.7 Pfizer-Provided Training 
Pfizer will make available training material that provides information about the SAE reporting 
requirements for IIR studies like this. Principal Investigator will review this material and share it with any 
Study staff engaged in the reporting of SAEs. 
 
 
5.4.3 Non-Serious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF. 
The Sponsor PI will forward periodically listings of non-serious AEs originating from the study to Pfizer. 
 
5.4.3.1 MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within the Event Description of the MedWatch 3500A 
form: 
assigned) 
 
 
suspect medication 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
 
 
5.4.4 Sponsor PI Reporting Requirements to Regulatory Authorities 
Adverse event reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.  
 
5.4.4.1 Seven Calendar Day Telephone or Fax Report: 
The Sponsor PI is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of palbociclib. An 
unexpected adverse event is one that is not already described in the palbociclib Investigator Brochure. 
Such reports are to be telephoned or faxed to the FDA and Pfizer within 7 calendar days of first learning 
of the event. 
 
5.4.4.2 Fifteen Calendar Day Written Report 
The Sponsor PI is also required to notify the FDA and all participating investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related to the use 

 
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of Palbociclib. An unexpected adverse event is one that is not already described in the Palbociclib 
investigator brochure. 
Written IND Safety reports should include an Analysis of Similar Events in accordance with regulation 21 
CFR § 312.32. All safety reports previously filed by the Sponsor PI with the IND concerning similar events 
should be analyzed and the significance of the new report in light of the previous, similar reports 
commented on. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Pfizer and all 
participating investigators within 15 calendar days of first learning of the event. The FDA prefers these 
reports on a MedWatch 3500 form, but alternative formats are acceptable (e.g., summary letter). 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to Pfizer 
U.S. Clinical Trial Department at 
 (Cover sheet at Appendix K) 
 
And to the Site IRB: 
MedStar Georgetown University Hospital - Institutional Review Board 
SW104 Medical Dental Building 
3900 Reservoir Road, NW 
Washington, DC. 20057 
 
 
  
 
5.4.5 Reporting Forms: 
Principal Investigator will report SAEs using a CIOMS I form (http://www.cioms.ch/index.php/cioms-
form)  or MedWatch 3500A (available at http://www.fda.gov/medwatch/getforms.html ). The 
Reportable Event Fax Cover Sheet (Appendix K) provided by Pfizer must also be included with each SAE 
submitted. 
The SAE Reporting Checklist is below: 
Use DD/MMM/YYYY format. 
Record all pertinent information on the SAE Report Form. Do NOT attach source documents 
(e.g., test results).  
Do NOT delay completing and submitting the SAE Report Form in order to obtain further 
information that could be submitted as a follow-up report. 
If a definitive assessment of causality is not possible at the time of the report, provide a 
preliminary assessment on the SAE page, and identify it as such in the Event Narrative. 
If the SAE is not deemed causally related to a study drug by the investigator, indicate in the Event 
Narrative the most likely cause (disease under study, other illness, etc.). 
If additional space is needed for any field, use additional copies of the same page. 

 
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Use a new SAE Report Form when providing follow-up information or responding to queries. Do 
NOT cross out or add to the previous form. 
Obtain safety reporting contact information for your study from your Pfizer contact. 
Confirm not only that a faxed SAE Report Form was transmitted successfully, but also that it was 
transmitted to the correct fax number. 
 
5.4.6 IND Annual Reports 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to Pfizer.  
 
5.4.7 Data Safety Monitoring Committee 
As this study is an investigator initiated study utilizing FDA approved agent it is considered a moderate 
risk study which requires real-time monitoring by the Sponsor PI and study team and semiannual 
reviews by the LCCC Data and Safety Monitoring Committee (DSMC). 
The Principal Investigator and the Co-Investigators will review the data including safety monitoring at 
weekly disease group meetings and on monthly network disease group teleconferences. The 
investigators shall meet regularly to review toxicities and follow up on results of patients enrolled on the 
study. 
Progress on the trial and the toxicities experienced will be reviewed by the Lombardi Comprehensive 
Cancer Center Data and Safety Monitoring Committee every 6 months from the time the first patient is 
enrolled on the study. Results of the DSMC meetings will be forwarded to the IRB. E-mail notification 
from the Sponsor PI will be sent to the DSMC Chair any time there is a major event or issue with the trial 
affecting patient safety or conduct of the trial. The DSMC Chair has the discretion to have the study 
reviewed by the DSMC sooner more frequently than every 6 months based on information received. 
All Severe Adverse Events (SAEs) are required to be reported to the IRB. In addition, all SAEs will be 
submitted to the DSMC at time of submission to IRB and to Pfizer. Based on SAEs, the IRB retains the 
authority to hold accrual for the study pending more detailed reporting and/or modifications to further 
reduce risk and maximize the safety of participating patients. DSMC recommendations should be based 
not only on results for the trial being monitored as well as on data available to the DSMC from other 
studies. It is the responsibility of the Sponsor PI to ensure that the DSMC is kept apprised of non-
confidential results from related studies that become available. It is the responsibility of the DSMC to 
determine the extent to which this information is relevant to its decisions related to the specific trial 
being monitored. 
A written copy of the DSMC recommendations will be given to the trial Sponsor PI and the IRB. If the 
DSMC recommends a study change for patient safety or efficacy reasons the investigator must act to 
implement the change as expeditiously as possible. In the unlikely event that the Sponsor PI does not 
concur with the DSMC, then the Lombardi Cancer Center Associate Director of Clinical Research must be 
informed of the reason for the disagreement. The Sponsor PI, DSMC Chair, and the Lombardi Cancer 
Center ADCR will be responsible for reaching a mutually acceptable decision about the study. 
Confidentiality must be preserved during these discussions. However, in some cases, relevant data may 
be shared with other selected trial investigators and staff to seek advice to assist in reaching a mutually 
acceptable decision. 

 
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If a recommendation is made to change the trial for reasons other than patient safety or efficacy the 
DSMC will provide an adequate rationale for its decision. 
 
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN  
 
6.1 Determination of Sample Size  
There will be two participating centers in this study: MGUH and MWHC. This is a prospective pilot study 
designed to assess the feasibility and potential translational changes of preoperative treatment with 
palbociclib of patients with Rb positive DCIS of the breast. The primary endpoints are feasibility and 
pathologic changes (histology, IHC and molecular analysis) comparing paired samples from before and 
after short course of systemic treatment (diagnostic core vs definitive surgery, in each patient). The 
secondary endpoint is descriptive toxicity.  
The estimated sample size of 12 patients per study Group is decided based on typical sample size 
requirement for a pilot study56 because parameters for expected pathologic changes caused by 
palbociclib in this disease are not available. The total number of patients in this study will be 24. The 
statistical analysis will be mostly descriptive due to the nature of the study and the small sample size. It 
will be performed after study completion. Baseline and follow-up data will be summarized using basic 
descriptive statistics such as means and standard deviations for the continuous variables and 
frequencies and percentages for categorical variables. For continuous outcome, the median and range 
will be reported. For binomial outcome, the proportion will be estimated along with its confidence 
interval estimated using exact method. Changes in the tumor histologic or molecular parameters from 
baseline to end of treatment will be tested using paired t-tests for continuous variables and McNemar's 
test for paired proportions. Repeated measures data will be analyzed using linear growth curve models 
that will allow us to identify and estimate individual-level growth tracks for the patients. Survival models 
(time to event) will be used as sample size permits to evaluate disease progression among all patients. 
LCCC Biostat Unit will be responsible for designing the study and conducting data analysis which will be 
directed by Dr. Ming Tan. 
 
 
7. DATA COLLECTION AND MANAGEMENT   
 
7.1 Data Quality Assurance 
During study conduct, the MedStar Georgetown University Hospital/Lombardi Comprehensive Cancer 
Center Quality Assurance Office (QAO) and/or Project Manager(s) (PM) will conduct periodic monitoring 
to ensure that the protocol and Good Clinical Practices (GCPs) are being followed. The LCCC/QAO or PM 
monitors may review source documents to confirm that the data recorded on CRFs is accurate. The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification. 

 
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The study site may be subject to review by the IRB, and/or to quality assurance audits performed by 
Pfizer, or companies working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities. It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the process. 
 
7.2 Electronic Case Report Forms 
As used in this protocol, the term CRF should be understood to refer to an electronic data record. A CRF 
is required and should be completed for each included patient. 
 
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety and 
laboratory data entered on the CRFs and any other data collection forms (source documents) and 
ensuring that they are accurate, authentic / original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring and available when required. Laboratory results and concomitant 
medications will be collected on the CRFs. The CRFs must be signed by the investigator or by an 
authorized staff member to attest that the data contained on the CRFs is true. Any corrections to entries 
made in the CRFs or source documents must be dated, initialed and explained (if necessary) and should 
not obscure the original entry.  
 
7.3 Source Data Documentation 
In most cases, the source documents are the hospital's or the physician's patient chart. In these cases, 
data collected on the CRFs must match the data in those charts. In some cases, the CRF, or part of the 
CRF, may also serve as source documents. In these cases, a document should be available at the 
for which the CRF will stand as the source document. 
 
7.4 Retention of Records 
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator agrees to 
keep records, including the identity of all participating patients (sufficient information to link records, 
e.g., CRFs and hospital records), all original signed informed consent documents, copies of all CRFs, 
safety reporting forms, source documents, and detailed records of treatment disposition, and adequate 
documentation of relevant correspondence (e.g., letters, meeting minutes, telephone calls reports). The 
records should be retained by the investigator according to International Conference on Harmonization 
(ICH), local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is longer. 
 
If the investigator becomes unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), Pfizer should be prospectively notified. The study records must be 
transferred to a designee acceptable to Pfizer, such as another investigator, another institution, or to an 
independent third party arranged by Pfizer. Investigator records must be kept for a minimum of 15 years 
after completion or discontinuation of the study or for longer if required by applicable local regulations. 

 
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The investigator must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met. 
 
 
8. ETHICAL CONSIDERATIONS  
 
8.1 Institutional Review Board or Ethics Committee 
All oncology clinical research protocols must be submitted to the Clinical Research Committee (CRC) for 
scientific review before submission to and final approval by the IRB. The initial review includes an 
assessment of the specific plans for data and safety monitoring, which vary depending on the study 
type, phase, size, and sponsorship. 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB should approve the consent form and protocol. In obtaining and 
documenting informed consent, the investigator should comply with the applicable regulatory 
requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles that have 
their origin in the Declaration of Helsinki.  
It is the responsibility of the investigator to have prospective approval of the study protocol, protocol 
amendments, informed consent documents, and other relevant documents, e.g., recruitment 
advertisements, if applicable, from the IRB. All correspondence with the IRB/EC should be retained in 
the Investigator File. Copies of IRB approvals should be forwarded to Pfizer. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on GCP, and 
applicable local regulatory requirements and laws. 
 
8.2 Informed Consent  
This study will be conducted in accordance with FDA regulations, the International Conference on 
Harmonization (ICH) E6 Guideline for Good Clinical Practice (GCP), the Declaration of Helsinki, and 
applicable local, state, and federal laws. The informed consent/assent document(s) used during the 
informed consent process must be reviewed by the Sponsor, approved by the IRB before use, and 
available for inspection. The investigator must ensure that each study patient, or his/her legally 
acceptable representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. Whenever consent is obtained from a patient's legally acceptable 
subject has the capacity to provide assent, as determined by the IRB/EC. If the investigator determines 
IRB and consistent with local regulatory and legal r
waived with source documentation of the reason assent was not obtained. If the study patient does not 
provide her own consent, the source documents must record why the patient did not provide consent 
(e.g., decisionally impaired adult), how the investigator determined that the person signing the consent 

 
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. If assent is obtained verbally it must be 
documented in the source documents. 
 
The investigator, or a person designated by the investigator, will obtain written informed consent from 
each patient or the patient's legally acceptable representative before any study- specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB. The investigator will retain 
the original of each patient's signed consent/assent document. 
 
Patients will be informed that participation is voluntary and not necessary for receiving standard of care 
chemotherapy for their cancer and that they can choose to withdraw consent from the study at any 
time. This will also be documented in writing on the consent form. 
 
The study will not include participants less than 18 years of age. For adult participants who lack decision-
making capacity, the legally authorized representative will serve as the proxy. In the event a patient or 
their proxy does not read, write, or understand English, a trained medical interpreter must be present, 
either in person or via phone or video remote access, to translate. 
 
8.3 Subject Compensation 
Subjects will not be compensated in cash or in kind. 
 
8.4 Confidentiality  
All parties will ensure protection of patient personal data and will not include patient names or other 
identifiable data in any reports, publications, or other disclosures, except where required by laws. 
Personal information about the patients, including but not limited to name, date of birth, sex, race, 
ethnicity, previous treatment (including but not limited to pathology reports, imaging reports, 
laboratory reports, surgery, radiation oncology, medical oncology, etc.), office notes, physical exam, 
history, medications, adverse events, etc. will be collected on each study patient. This data is important 
for evaluating the primary and secondary endpoints of the study and will be protected from improper 
use and disclosure as per MedStar standard operating procedures. This plan will be implemented at the 
time of signing consent for each patient.  
Protected Health Information (PHI) will be accessed in this study. PHI will be received via a CRF and also 
be recorded in a CRF. PHI information will be retained until all follow up publications and studies 
stemming from this study have been completed. This information will only be shared within the 
research team. Confidentiality will be maintained via standard MedStar standard operating procedures. 
All electronic transmission of PHI data will be in encrypted/secured form. No names of subjects will be 
included in the publication. No digital, video, audio, or photographic recordings of the subject will be 
made public. 
When study data is compiled for transfer to any authorized parties, patient names, addresses and other 
identifiable data will be replaced by a numerical code consisting of a numbering system in order to de-
identify study patients. The study site will maintain a confidential list of subjects who participated in the 
s actual identity. In case of data transfer, Pfizer will 

 
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maintain high standards of confidentiality and protection of patient personal data consistent with 
applicable privacy laws. 
All hardcopy and electronic data will be kept in accordance with the MedStar standard operating 
procedures. Upon completion of all publications related to this study, the data will be destroyed in 
accordance with institutional protocols. No members other than those on the research team will have 
access to the study data. Data will not be shared outside of the research team. 
 
8.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable Competent 
Authority, or if the investigator is aware of any new information which might influence the evaluation of 
the benefits and risks of the investigational product, Pfizer should be informed immediately. 
 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures taken by the 
investigator to protect the study patients against any immediate hazard, and of any serious breaches of 
this protocol or of ICH GCP that the investigator becomes aware of. Except for an emergency situation in 
which proper care for the protection, safety, and well-being of the study patient requires alternative 
treatment, the study shall be conducted exactly as described in the approved protocol. 
 
a. Emergency Modifications: Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB approval. For any 
such emergency modification implemented, an IRB modification form must be completed within 
five (5) business days of making the change. 
 
b. Single Patient/Subject Exceptions: Any request to enroll a single subject who does not meet all the 
eligibility criteria of this study requires the approval of the Principal Investigator and the IRB. 
c. Other Protocol Deviations/Violations: All other planned deviations from the protocol must have 
prior approval by the Principal Investigator and the IRB. According to the IRB, a protocol deviation 
is any unplanned variance from an IRB approved protocol that: 
 
tantive effect on the risks to research participants 
collected 
 
 
An unplanned protocol variance is considered a violation if the variance: 
 
 
 
knowing misconduct on the part of the investigator(s). 

 
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University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, please follow the 
guidelines below: 
A) Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring 
committee in accordance with their policies. Minor deviations should be summarized and 
reported to the IRB at the time of continuing review. Major deviations should be summarized 
and reported to the Regulatory Affairs Coordinator who will submit to the IRB as soon as 
possible, but not more than 10 calendar days after acquiring information reasonably suggesting 
that a reportable (major) deviation has occurred. 
 
B) Protocol Violations: Violations should be reported by study personnel within one (1) week of the 
investigator becoming aware of the event using the same IRB online mechanism used to report 
Unanticipated Problems. 
 
8.6 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and documented 
by the Principal Investigator. It should also be noted that when an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent form might be 
required. The written amendment, and if required the amended consent form, must be sent to the IRB 
for approval prior to implementation. 
 
8.7 Financial Disclosure  
Investigators will provide Pfizer and regulatory authorities with adequate and accurate financial 
information in accordance with local regulations and laws in order to allow Pfizer to submit complete 
and accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing updated information on financial interests during the course 
of the study as well as for 1 year after completion of the study. 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by 
MHRI or LCCC. All investigators will follow the MHRI and LCCC conflict of interest policy. 
 
8.8 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, the study shall be conducted exactly as described in the 
approved protocol. Minor deviations should be summarized and reported to the IRB at the time of 
continuing review. Major deviations should be summarized and reported to the Regulatory Affairs 
Coordinator who will submit to the IRB as soon as possible, but not more than 10 calendar days after 
acquiring information reasonably suggesting that a reportable (major) deviation has occurred. 

 
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9. REQUIRED DOCUMENTATION  
 
 
Before the study can be initiated at any site, the following documents must be filed at MGUH Regulatory 
(Study Binder): 
Original U.S. FDA Form 1572. The names of all investigators must appear on this form. 
Investigators must also complete all regulatory documentation as required by local and national 
regulations; 
Sponsor-
-
urrent curriculum vitae 
Written documentation of IRB approval of protocol and informed consent document; 
A copy of approved protocol  
A copy of the IRB-approved informed consent document and IRB communications;  
CRC communication  
A signed Clinical Research Agreement  
Delegation of authority log  
Lab CAP/CLIA, Laboratory normals  
Any sponsor communication, including newsletters  
Monitoring visits letters  pre/post 
 
 
 
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Appendix A: Study procedures  
 
 
 
 

 
Protocol WI223281  Palbociclib in DCIS  Mainor 
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1 Rb testing for all participants at screening. Rb negative configures screen failure. 
 
 
 
2 Research blood sample for liquid biopsy and tissue banking (serum/plasma and PBMCs). In Group B, 
pre-operative sample can be drawn any time after consenting and prior to surgery. For details on 
these samples please refer to item 4.5.2.7 Mandatory Blood Samples for Biomarker Analysis 
 
3 Palbociclib 100mg PO daily for 12 days; provided by Pfizer and to be dispensed by MGUH/WHC 
research pharmacy.  
 
 
 
 
 
 
 
4 Group A only.  
 
5 Tissue sample #2: Under supervision of the certified pathologist, the sample required for pathologic 
diagnosis will be collected. Excess tissue will be used for research. Research tumor samples will be 
collected for H&E and IHC (formalin), CRC cultures (conditionally reprogrammed cell media), 
isolation of RNA and subsequent expression analysis, and for proteomic or metabolomic analysis 
(Snap Frozen). Non used tissue will be banked. Handling, processing, storage and testing DCIS 
sample at definitive surgery by pathologist and at Lombardi Research Lab (RIEGEL LAB) 
 
 
6 Evaluation of clinical characteristics including disease status by EMR review and telephone contact 
 
7 Additional visits will be required for patients enrolled on Group A. These include a visit with Medical 
Oncology team prior to initiation of palbociclib (pre-Treatment) and another visit after end of 
palbociclib, prior to surgery (pre-Surgery). These visits are not required for patients enrolled in 
Group B. 
 
8 Tests must be completed at least 5 days prior to definitive surgery in Group B (untreated) 
9 Clinical visit (28) to (-)1 is the routine visit typically with the surgeon to discuss newly diagnosed DCIS 
and surgical plan, at which point the study may be offered to the patient (Group A and B). 
 
 

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Appendix B: Study schema 
Group A
Palbociclib treatment:
§ Please refer to item 4.5.2.7 Mandatory Blood Samples for Biomarker Analysis

 
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Group B  tissue only: 
 
 
* Please refer to item 3.1.1 Overview of Study Design, timing of surgery, for additional details on 
definitive surgery timing after enrollment for patients on Group B (no palbociclib). 
§ Please refer to item 4.5.2.7 Mandatory Blood Samples for Biomarker Analysis  
 

 
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Appendix C: Calendar for treatment planning based on surgery date 
for Group A patients   
  
 

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Appendix D: Enrollment Process to Treatment Overview

Protocol WI223281  Palbociclib in DCIS  Mainor 
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ON-STUDY CARD  Study 2018-0075  
MRN: _______________________ 
DOB: ______/______/_____________ 
Treating Physician ____________________ RN_________________________________ 
Zip Code: ___________ 
Race  (   ) African American 
(   ) Asian 
(   ) Caucasian 
(   ) Hispanic 
(   ) Native American 
(   ) Pacific Islander 
(   ) Other 
(   ) Unknown 
Gender:     
(   ) Male              (   ) Female               (   ) Unknown 
Ethnicity:    
(   ) Hispanic or Latino 
(   ) Not Hispanic or Latino 
(   ) Unknown 
Consent Approval Date: ______/______/____________ 
Screen Failure  
(   ) Yes  
(   ) No 
On Study Date ______/______/____________ 
Protocol Waiver:  
(   ) Yes  
(   ) No 
Reason _________________ 
First Scheduled Treatment Date (Group A only): ______/______/____________ 
 
 
FOR LCCC-PM USE ONLY: 
Eligibility verified:    
(   ) Yes  
(   ) No 
Subject Study ID: _________________________________ 
PM name: _______________________ Signature: ________________  
Date _____/_____/__________ 

Protocol WI223281  Palbociclib in DCIS  Mainor 
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Appendix G: Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
 
 
 
As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982.57 
 
 
 

Protocol WI223281  Palbociclib in DCIS  Mainor 
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Appendix J: Palbociclib Diary (Group A) 
Patient #: ______________________   Date (mm-dd-yyyy) ______ / ______ / ____________  
Treatment start date (mm-dd-yyyy) ______ / ______ / ____________ 
Treatment end date (mm-dd-yyyy) ______ / ______ / ____________ 
Study 2018-0075  
Day 
Date             
(MM-DD-YYYY) 
Time                           
(write the time you took 
palbociclib in hh:mm format) 
Comments 
1 
  
  
  
2 
  
  
  
3 
  
  
  
4 
  
  
  
5 
  
  
  
6 
  
  
  
7 
  
  
  
8 
  
  
  
9 
  
  
  
10 
  
  
  
11 
  
  
  
12 
  
  
  
 
-day pre-operative treatment course. The treatment 
may start on any calendar date; thus a Treatment Day does not usually match the 
calendar date.  
Take one capsule of Palbociclib 100 mg by mouth with water daily at approximately the 
same time each day. Palbociclib should be taken with food.  

Protocol WI223281  Palbociclib in DCIS  Mainor 
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Appendix L: Pathology Form 
 
Preoperative palbociclib in patients with DCIS of the breast that are candidates for surgery: WI223281 
 
Subject Registration Number on Study: _________   
Study ID (IRB#): 2018-0075  
Date _____/_____/__________ 
Name of Pathologist: _________________________ Signature: ________________ 
 
Person filling the form if different than pathologist:  
_______________________ Signature: ________________  
 
Definitive surgery:  
 Mastectomy    
 Lumpectomy 
Check list: 
Sample collected for routine pathology exam 
 
Research sample: 
No sample available for Research 
Sample collected for research 
 
Research procedures: 
 
Sample in CRC media 
 date: ____/_____/________ 
Time: ____:_____AM/PM 
By _______________________ (Name) 
 
 
 
 

Protocol WI223281  Palbociclib in DCIS  Mainor 
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Appendix M: Research Blood Sample Form 
 
Preoperative palbociclib in patients with DCIS of the breast that are candidates for surgery: WI223281 
 
Subject Registration Number on Study: _________   
Study ID (IRB#): 2018-0075  
Date _____/_____/__________ 
Name of Study Coordinator: _________________________ Signature: ________________ 
----------------------------------------------------------------------------------------------------------------------------------------- 
What is this the time point of this research blood sample? 
 
Group A (palbociclib) 
Blood sample #1 (pre-palbo) 
o
Plasma 
o
PBMC 
Blood sample #2 (pos-palbo and pre-
surgery) 
o
Plasma 
o
PBMC 
Blood sample #3 (post-surgery) 
o
Plasma 
o
PBMC 
 
Group B (observation) 
Blood sample #1 (pre-palbo) 
o
Plasma 
o
PBMC 
Blood sample #2 (post-surgery) 
o
Plasma 
o
PBMC 
 
 
 
 
----------------------------------------------------------------------------------------------------------------------------------------- 
 date: ____/_____/________ 
Time: ____:_____AM/PM 
By _______________________ (Name)