Conditions: Hormone Receptor Positive HER-2 Negative Breast Cancer
Keywords: African American
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
This study aims to evaluate the hematological safety of palbociclib with letrozole and fulvestrant in African American women with hormone receptor positive HER2 negative advanced breast cancer. Hematological safety is a composite endpoint of episodes of febrile neutropenia and treatment discontinuation due to neutropenia according to current recommendations for management of neutropenia

Detailed description:
The study is designed to assess the rate of completion of planned oncology therapy in the absence of a hematological event defined as episodes of febrile neutropenia and treatment discontinuation due to neutropenia. A completion rate of 80% is considered of clinical relevance as to benefit breast cancer patients who are at a higher risk of having ethnic neutropenia where as a completion rate of 60% is considered poor and to justify additional safety studies. A two stage design with a total of 35 patients is used to test if the completion rate is at least 80% versus if it is below 60% with 80% power at a significance level of 5%.

An exact confidence interval of the completion rate will be calculated. Investigators estimate there will be no more than a 10% rate of febrile neutropenia. Due to the small sample size, the analysis of secondary endpoints will be descriptive and will not include specific hypothesis testing.

Arms:
arm 1: None

Interventions: intervention 1: Palbociclib + Letrozole or Fulvestrant
Intervention descriptions: intervention 1: Palbociclib x 21 days with a 7 day rest plus 2.5 mg Letrozole QD (no break) or Fulvestrant 500mg IM every 2 weeks for 3 doses and then every 4 weeks until progression or maximum of 12 months

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
Phase II Safety Study of Palbociclib in Combination with Letrozole or Fulvestrant in 
African American Women with Hormone Receptor Positive HER2 Negative Advanced 
Breast Cancer (PALINA study)  
  
Principal Investigator:   
Filipa Lynce, MD  
Assistant Professor of Medicine  
Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital  
  
Study Statistician:   
Ming Tan, PhD  
  
Sub-Investigators:  
Georgetown MedStar Cancer Network:   
Claudine Isaacs, MD  
Paula Pohlmann, MD PhD  
Christopher Gallagher, MD  
Robert Warren, MD  
Asma Dilawari, MD  
Mahsa Mohebtash, MD  
Lois Kamugisha, MD  
  
University of Chicago  
Olwen Hahn, MD  
  
Thomas Jefferson University  
Maysa Abu-Khalaf, MD  
  
  
Basic science investigators:  
Ayesha Shajahan-Haq, PhD  
Robert Clarke, PhD  
  
Study Drugs: Palbociclib  
  
Funding Source: Pfizer  
  
Initial version: 1/04/2016  
  
  
V5 06.05.2018  
  
  
 
 
 
 
 
 
 


2 
 
Signature Page  
  
  
Phase II Safety Study of Palbociclib in Combination with Letrozole or Fulvestrant in 
African American Women with Hormone Receptor Positive HER2 Negative Advanced 
Breast Cancer  
  
Protocol No.:    
 
 
 
 
Version date:                                                                         
  
  
The signature below constitutes the approval of this protocol and the attachments, and provides  
the necessary assurances that this trial will be conducted according to all stipulations of the  
protocol, including all statements regarding confidentiality, and according to local legal and  
regulatory requirements and applicable U.S. federal regulations and International Conference  
on Harmonization (ICH) guidelines.  
  
  
  
Principal Investigator (PI) Name:________________________________________________  
  
PI Signature: ________________________________________________________________  
  
Date: _______________________________________________________________________  
  
Name of Site: ________________________________________________________________  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
  
  
  
 
  
 
  
 
 


3 
 
TABLE OF CONTENTS  
  
  
  
STUDY SUMMARY....................................................................................................................................7  
  
1. INTRODUCTION ...................................................................................................................................10  
  
  
1.1. Background............................................................................................................................10 
  
1.2. Palbociclib…………………………………………………………………………………………. 10 
 
   
 
1.2.1. Preclinical Data......................................................................................................10 
  
 
 
1.2.2. Clinical activity…………………………………………………………………………..11 
  
  
 
1.2.3. Toxicity …………….................................................................................................12  
  
  
1.3. Minorities enrollment in clinical trials………………………………….………………………….13  
  
  
1.4. Neutrophil count in African Americans………………………………………….………………...13  
  
  
1.5. Metabolomics and exosomes in endocrine resistance………………………………………….14  
  
  
1.6. Study Rationale ......................................................................................................................14  
  
2. STUDY OBJECTIVES AND ENDPOINTS .............................................................................................15  
  
  
2.1. Objectives .............................................................................................................................15  
  
  
2.2. Endpoints................................................................................................................................16  
  
3. STUDY DESIGN.....................................................................................................................................16  
  
4. PATIENT SELECTION ..........................................................................................................................18  
  
  
4.1. Inclusion Criteria ....................................................................................................................18  
  
  
4.2. Exclusion Criteria....................................................................................................................19  
  
5. STUDY TREATMENTS..........................................................................................................................19  
  
  
5.1. Allocation to Treatment ..........................................................................................................20  
  
  
5.2. Compliance.............................................................................................................................20 
  
  
5.3. Drug Supplies ........................................................................................................................20  
  
   
 
5.3.1. Dosage Form(s) and Packaging ............................................................................20  
  
    
 
 
5.3.1.1. Palbociclib ..............................................................................................20  
 
    
 
 
5.3.1.2. Letrozole.................................................................................................20 
  
    
 
 
5.3.1.3. Fulvestrant…………………………………………………………………...20  
 
 
 
 
 
 
 
5.3.1.4. Anastrozole…………………………………………………………………..20 
 
 
 
 
 
 
 
5.3.1.5 Exemestane…………………………………………………………………..20 


4 
 
  
   
 
5.3.2. Preparation and Dispensing – Palbociclib……………………………………………21 
  
   
 
5.3.3. Administration.........................................................................................................21 
  
    
 
 
5.3.3.1. Palbociclib...............................................................................................21 
  
    
 
 
5.3.3.2. Letrozole.................................................................................................22  
  
    
 
 
5.3.3.3. Fulvestrant………………………………………………………………….. 22  
 
 
 
 
5.3.3.4. Anastrozole…………………………………………………………………..22 
 
 
 
 
5.3.3.5. Exemestane………………………………………………………………….22  
  
   
 
5.3.4. Recommended Dose Modification .........................................................................22  
     
    
 
 
5.3.4.1. Dosing Interruptions/Delays - Palbociclib………………………………...23  
  
    
 
 
5.3.4.2. Retreatment Criteria – Palbociclib..........................................................23 
  
    
 
 
5.3.4.3. Dose Reductions - Palbociclib ...............................................................24  
  
  
5.4. Drug Storage ..........................................................................................................................25  
  
  
5.5. Drug Accountability.................................................................................................................26 
 
  
5.6. Concomitant Medication(s)………………………………………………………………………...26  
  
   
 
5.6.1. Prohibited Medications ...........................................................................................27 
  
   
 
5.6.2. Medications Not Recommended.............................................................................27  
  
6. STUDY PROCEDURES……………………………………………………………………………………….28  
  
6.1. Schedule of events ................................................................................................................28  
   
  
6.2. Patient Withdrawal..................................................................................................................30  
 
7. ASSESSMENTS.....................................................................................................................................31  
  
  
7.1. Safety Assessments...............................................................................................................31 
 
   
 
7.1.1. Physical Examination .............................................................................................31  
  
   
 
7.1.2. Laboratory Safety Assessments.............................................................................31 
  
  
7.2. Tumor Assessments...............................................................................................................32  
  
8. ADVERSE EVENT REPORTING...........................................................................................................32  
  
  
8.1. Adverse Events......................................................................................................................32  
  
  
8.2. Reporting Period ....................................................................................................................33  
  
  
8.3. Definition of an Adverse Event...............................................................................................33  
  
   
 
8.3.1. Medication Errors………………………………………………………………………..34 
  


5 
 
  
8.4. Abnormal Test Findings.........................................................................................................34  
  
  
8.5. Serious Adverse Events.........................................................................................................35  
  
   
 
8.5.1. Protocol-Specified Serious Adverse Events...........................................................35  
  
  
8.6. Hospitalization .......................................................................................................................35  
   
  
8.7. Severity Assessment..............................................................................................................36  
 
  
8.8. Causality Assessment ............................................................................................................36  
  
8.9. Withdrawal Due to Adverse Events……………………………………………………………….37 
  
  
8.10. Eliciting Adverse Event Information .....................................................................................37  
  
  
8.11. Reporting Requirements.......................................................................................................37  
  
   
 
8.11.1. Serious Adverse Event Reporting Requirements.................................................37 
  
   
 
8.11.2. Non-Serious Adverse Event Reporting Requirements..........................................39  
  
   
 
8.11.3. Sponsor Reporting Requirements to Regulatory Authorities................................39 
  
9. CORRELATIVE STUDIES……………………………………………………………………………………..39  
  
10. DATA ANALYSIS/STATISTICAL METHODS ......................................................................................40  
  
  
10.1. Two stage design, Sample Size, Accrual and Study duration .............................................40  
  
  
10.2. Statistical analysis plan.........................................................................................................41  
  
  
10.3 Safety stopping rules.............................................................................................................41   
  
  
10.4. Safety Analysis.....................................................................................................................42  
  
  
10.5. Data Safety Monitoring Committee ......................................................................................42  
  
11. QUALITY CONTROL AND QUALITY ASSURANCE............................................................................43  
  
12. DATA HANDLING AND RECORD KEEPING ......................................................................................44  
  
  
12.1. Case Report Forms/Electronic Data Record ........................................................................44  
  
  
12.2. Record Retention..................................................................................................................44 
  
13. ETHICS.................................................................................................................................................45  
  
  
13.1. Institutional Review Board (IRB)………………………………………………………………….45 
  
  
13.2. Ethical Conduct of the Study……………………………………………………………………...45 
  
  
13.3. Patient Information and 
Consent...........................................................................................45 
  
  
13.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP....................46  
  
  
13.5 Amendments to the protocol……………………………………………………………………….48 


6 
 
 
14. REFERENCES 
.....................................................................................................................................48  
  
  
 
LIST OF TABLES  
  
Table 1. Study summary ..............................................................................................................................7  
  
Table 2. Available Dose Levels .................................................................................................................24  
  
Table 3. Palbociclib Dose Modifications for Treatment Related Hematologic Toxicities ...........................25  
  
Table 4. Palbociclib Dose Modifications for Treatment Related non-Hematologic Toxicities ....................25  
  
Table 5. Schedule of Events …..................................................................................................................28  
  
Table 6. Probability table for febrile neutropenia .......................................................................................42  
  
  
  
LIST OF FIGURES  
  
Figure 1. Study design……………………………………………………………………………………………16  
  
  
  
APPENDICES  
  
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status ....................................50  
  
Appendix 2. List of Abbreviation ................................................................................................................51  
  
Appendix 3. Patient Medication Diary…………………………………………………………………………...52  
  
  
  
  
  
  
  
   
  
  
  
  
 
 
 
 
 
 
 
  
  
  
 
 


7 
 
 
 
STUDY SUMMARY   
  
Table 1. Study summary  
  
Title  
Phase II safety study of palbociclib in combination with letrozole or 
fulvestrant in African American women with hormone receptor positive 
HER2 negative advanced breast cancer  
Protocol Number  
2015-1396  
Phase  
Phase II study  
Study Duration  
24 months; enrollment over 12 months   
 
Study Center(s)  
The study will open at the Georgetown MedStar Cancer Network, 
University of Chicago and Thomas Jefferson University  
 
 
 
 
Primary Objective  
To evaluate the hematological safety of palbociclib with letrozole or 
fulvestrant in African American women with hormone receptor positive 
HER2 negative advanced breast cancer. Use of anastrozole or 
exemestane permitted in the event of letrozole intolerance.  
Hematological safety is a composite endpoint of episodes of febrile 
neutropenia and treatment discontinuation due to neutropenia 
according to current recommendations for management of neutropenia  
 
 
 
 
 
 
Secondary 
Objectives  
 
• To evaluate delays in palbociclib therapy attributed to neutropenia  
• To evaluate dose reductions in palbociclib therapy attributed to       
 neutropenia  
• To evaluate grade 3/4 neutropenia  
• To evaluate the efficacy of palbociclib with letrozole or fulvestrant in 
 African American women with ER/PR positive HER2 negative     
 metastatic breast cancer with evaluable disease. Use of anastrozole  
 or exemestane permitted in the event of letrozole intolerance.          
• To evaluate correlations between proliferation rates and efficacy  
• To describe baseline absolute neutrophil count (ANC) prior to cancer  
 diagnosis and the Duffy Null polymorphism (SNP rs2814778 at  
 chromosome 1q23.2) and explore correlations with hematological   
 safety  
 
 


8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Important inclusion 
and exclusion 
criteria  
Main inclusion criteria:  
 
1. Self-identified Black, African or African American women of ≥ 18 
years of age with proven diagnosis of advanced adenocarcinoma of 
the breast (locoregionally recurrent or metastatic disease)  
 
2. ER-positive and/or PgR-positive tumor based on local laboratory 
results  
 
3. HER2-negative breast cancer based on local laboratory results (test 
to be used as per local practice)  
 
4. Patients must be appropriate candidates for letrozole or fulvestrant 
therapy.  Use of anastrozole or exemestane permitted in the event of 
letrozole intolerance.   
 
5. Eastern Cooperative Oncology Group (ECOG) performance status 
0-2   
 
6. Adequate bone marrow function:  
 
- Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 (1.0 x 109/L);  
- Platelets ≥100,000/mm3 (100 x 109/L);  
- Hemoglobin ≥9 g/dL (90 g/L).  
  
Main exclusion criteria:  
 
1. Current use of food or drugs known to be potent inhibitors or 
inducers of CYP3A4  
 
2. Active uncontrolled or symptomatic brain metastases. Previously 
treated and clinically stable, as per Investigator’s judgment, brain 
metastases are permitted.  
 
3. Previous CDK4/6 inhibitor  
 
 
Primary endpoint  
 
Proportion of patients who complete planned oncologic therapy without 
the development of a hematological event defined as episodes of 
febrile neutropenia and treatment discontinuation due to neutropenia 
according to current recommendations for management of neutropenia  
 
 


9 
 
 
 
 
 
 
 
 
Secondary endpoint  
 
• Number of patients who required dose delays in palbociclib attributed  
 to neutropenia.          
• Number of patients who required dose reductions in palbociclib  
 therapy attributed to neutropenia 
• Rate of grade 3/4 neutropenia  
• Clinical benefit rate (for those with evaluable disease) at 24 weeks  
• To evaluate correlations between metabolite and exosomal signature  
 with disease response 
• To evaluate correlations between baseline ANC prior to cancer  
 diagnosis and the Duffy Null polymorphism (SNP rs2814778 at  
 chromosome 1q23.2) with hematological safety 
 
 
Correlative studies  
  
 
Metabolite biomarkers and exosomal signature of endocrine resistance  
 
Oncology study 
Products, Doses, 
Routes, Regimens  
Palbociclib 125mg once daily taken with food for 21 days followed by 7 
days off treatment. For patients enrolled with baseline ANC between 
1000 and 1499/uL, initial dose of palbociclib will be 100mg once daily 
for 21days followed by 7 days off treatment.  
Duration of drug 
administration   
Maximum of 12 months.   
 
 
 
 
 
 
 
Statistical 
Methodology  
The study is designed to assess the rate of completion of planned 
oncology therapy in the absence of a hematological event defined as 
episodes of febrile neutropenia and treatment discontinuation due to 
neutropenia. A completion rate of 80% is considered of clinical 
relevance as to benefit breast cancer patients who are at a higher risk 
of having ethnic neutropenia where as a completion rate of 60% is 
considered poor and to justify additional safety studies. A two stage 
design with a total of 35 patients is used to test if the completion rate is 
at least 80% versus if it is below 60% with 80% power at a significance 
level of 5%.   
 
An exact confidence interval of the completion rate will be calculated. 
We estimate there will be no more than a 10% rate of febrile 
neutropenia. Due to the small sample size, the analysis of secondary 
endpoints will be descriptive and will not include specific hypothesis 
testing.   
 
  
 
 
 
 
 


10 
 
1. INTRODUCTION  
  
1.1. 
Background 
  
Hormone receptor (HR) positive human epidermal growth factor receptor 2 (HER2) 
negative breast cancer is the most common subset of breast cancer.1 Most patients are 
diagnosed at an early stage and remain relapse-free if treated with a prolonged course of 
endocrine therapy. However, about one-third of patients with HR positive HER2 negative 
tumors, diagnosed initially with early stage disease, experience disease recurrence.2 The 
fundamental problem is that endocrine agents are only partially effective, typically causing cell 
cycle arrest and tumor dormancy rather than true cure.  
 
The role of estrogens in BC etiology and progression is well established. Modification of 
estrogen activity or synthesis represents the treatment of choice for post-menopausal women 
with HR positive advanced breast cancer, particularly for those with slowly progressive disease 
and limited tumor-related symptoms.3 Studies of estrogen receptor (ER) positive breast cancer 
cell lines indicate that estrogens4 and antiestrogens5 act on sensitive populations of cells in 
early to mid-G1 phase. G1/S transition is under the control of cyclin-dependent kinases (CDKs) 
activated by specific complex formation with regulatory cyclins.  
 
Conversion of androgens to estrogens via aromatase enzyme action represents the main 
source of estrogens in post-menopausal women. Letrozole is an oral nonsteroidal aromatase 
inhibitor that is approved worldwide for the first line treatment of post-menopausal women with 
HR positive advanced breast cancer. Letrozole is administered orally in a continuous regimen at 
a 2.5 mg daily dose. In a multicenter Phase III study in patients with HR positive or HR-unknown 
advanced breast cancer, letrozole was superior to tamoxifen for time to progression (TTP), time 
to treatment failure (TTF), overall response rate (ORR), and overall clinical benefit response 
(CBR).6 Multiple clinical studies have shown that letrozole is well tolerated.  
  
1.2. Palbociclib  
 
Palbociclib is a novel, first-in-class highly selective oral reversible inhibitor of CDK 4 and 6 that 
is being studied for use in the treatment of different cancers including breast cancer. The 
compound inhibits cell proliferation by preventing progression of the cell cycle from G1 into the 
S phase. In February 3, 2015 the FDA granted accelerated approval to palbociclib (IBRANCE®) 
in combination with letrozole for first-line therapy of postmenopausal women with locally 
advanced or metastatic ER-positive HER2-negative breast cancer.  
  
1.2.1. Preclinical Data  
 
Palbociclib inhibits purified CDK4-catalyzed phosphorylation of retinoblastoma protein with an 
IC50 of less than 20 nM, and also tumor growth of several types of human xenograft tumors 
(SF-295, MDA-MB-435, Colo-205, and others) grown in mice. Treatment of cultured tumor cells 
with palbociclib causes growth arrest that is accompanied by the inhibition of specific 
retinoblastoma (Rb) phosphorylation by CDK4 or CDK6 on residues serine -780 and -795 of Rb.    
 
 


11 
 
Palbociclib was tested in vitro on molecularly characterized human BC cell lines. Results from 
these experiments indicate that those cell lines that are more sensitive to palbociclib (IC50 <150 
nM) have low levels of CDKN2A (p16) and high levels of Rb1, while resistant cell lines show the 
opposite characteristics. Sensitive cell lines in this panel represent mostly the luminal ER 
positive subtype.7 The combination of palbociclib and aromatase inhibitors has not been tested 
in preclinical models.  However, the combination of palbociclib with tamoxifen has recently been 
tested in vitro in ER positive human breast cancer cell lines indicating a synergistic interaction7 
and provides a biologic rationale for evaluating the combination of palbociclib with antihormonal 
therapy in the clinic.  
 
Palbociclib preclinical data indicate that it may be expected to have direct effect on growth 
arrest as well as potential secondary cytotoxic activity.  
  
1.2.2. Clinical Activity 
  
Palbociclib was initially evaluated as a single agent in 2 phase I dose escalation trials in patients 
with advanced malignancies.8,9 In the first published trial, 33 patients with Rb-positive advanced 
solid tumors or non-Hodgkin lymphoma refractory to standard treatment received palbociclib 
once daily for 14 days followed by 7 days off (2 weeks on/1 week off).8 Overall it was well 
tolerated with dose-limiting toxicities (DLTs) related primarily to myelosuppresion. There was 1 
partial response (PR) and 9 patients had stable disease (SD). The recommended phase II dose 
(RP2D) was 200mg. In the second study,9 41 patients with Rb-positive advanced solid tumors 
were enrolled, including 5 patients with breast cancer. In this trial, palbociclib was administered 
on a different dose schedule, with 21 days on followed by 7 days off (3 weeks on/1 week off). 
Neutropenia was the only dose-limiting effect and the most common nonhematologic grade 3/4 
adverse events (AEs) included fatigue, nausea, and abdominal pain. Of the 37 patients 
evaluable for tumor response, 10 had SD. The RP2D was 125 mg. This study defined the 
dosage used for subsequent trials.   
 
The results seen in phase I led to a single arm phase II study of palbociclib given as 
monotherapy in patients with Rb-positive advanced breast cancer.10 Thirty-seven patients were 
enrolled and 19% had a CBR, defined as PR and SD for 24 months or longer. Median 
progression-free-survival (PFS) was 3.7 months overall but was significantly longer for those 
with HR positive disease compared with HR negative disease (4.5 vs 1.5 months, P = .03).   
 
Based on preclinical data demonstrating synergy of palbocliclib with anti-estrogen therapy7, Finn 
et al conducted the PALOMA-1 trial.11 This multicenter, open-label phase II trial enrolled 165 
postmenopausal women with ER positive HER2 negative, advanced breast cancer who had not 
received previous systemic treatment for advanced disease. Patients were randomized in a 1:1 
fashion to letrozole 2.5mg daily or letrozole 2.5mg daily plus palbociclib. Median investigator-
assessed PFS was 20.2 months (95% CI 13.8-27.5) in the palbociclib plus letrozole arm and 
10.2 months (95% CI 5.7-12.6) in the letrozole alone arm (hazard ratio [HR], 0.488, 95% CI 
0.319-0.748). In addition, the ORR in patients with measurable disease was higher in the 
palbociclib plus letrozole compared with the letrozole alone arm (55.4% vs 39.4%).   
 
 
While the results of the phase II study PALOMA-1 are encouraging, a phase III randomized 


12 
 
double-blind placebo controlled trial was designed to definitely evaluate the role of palbociclib in 
metastatic breast cancer: PALOMA-2.12 Eligible patients are postmenopausal women with ER-
positive HER2-negative disease who have not received prior therapy for advanced breast 
cancer, prior CDK 4/6 inhibitors, nor prior (neo)adjuvant treatment with letrozole or anastrozole 
with a disease free interval less than 12-months from completion of treatment. Patients were 
assigned to letrozole with palbociclib 125 mg once daily 3 weeks on/1 week off or to letrozole  
with placebo. This study has completed accrual and results are expected in 2016.   
 
Palbociclib has also been investigated in the second-line setting. In PALOMA-3 study, a phase 
III randomized (2:1) double blind study, 521 patients with HR-positive, HER2-negative breast 
cancer that relapsed or progressed on previous endocrine therapy were assigned to fulvestrant 
with palbociclib or placebo.13 Premenopausal or perimenopausal women were eligible if also 
treated with goserelin. Women on the experimental arm had more than double median PFS 
(primary endpoint) compared with those in the placebo arm (9.2 months vs 3.8 months, HR 
0.42, P <.001). The relative difference in primary outcome between the placebo and palbociclib 
groups was consistent regardless of menopausal status of the patients. At the time of this 
preplanned interim analysis, data on overall survival (secondary endpoint) were immature. 
Although the efficacy benefit was not as large as seen in the first-line setting, these results have 
led to an expansion of the currently approved label of palbociclib in breast cancer. In February 
2016 the FDA approved the use of palbociclib in combination with fulvestrant in women with 
HR+ HER2- advanced or metastatic breast cancer after progression on endocrine therapy.   
  
1.2.3. Toxicity  
 
Palbociclib is overall well tolerated, either as monotherapy or in combination with anti-estrogen 
therapies. However quite often dosage reductions or treatment delays are required primarily due 
to hematologic toxicity. In the phase I study reported by Flaherty KT et al,9 neutropenia was the 
dose-limiting toxicity and there was a relatively small incidence of grade 3 neutropenia (12%) 
and anemia (7%). Surprisingly in the single arm phase II study where palbociclib was also given 
as monotherapy, neutropenia was significantly higher and grade 3/4 neutropenia, anemia, and 
thrombocytopenia were reported in 51%, 5%, and 22% of patients, respectively. Of note, 24% of 
patients had treatment interruption and 51% had dose reductions, all due to cytopenias.10  
 
In the PALOMA-1 study11, the most common grade 3/4 toxicities were also hematologic. What 
seemed to be unexpected was the finding that although grade 3/4 neutropenia was reported in 
54% of patients in the experimental arm, no cases of febrile neutropenia or neutropenia-related 
infections were seen. Among the nonhematologic all-grade AEs, the most common were fatigue 
(40%), nausea (25%), arthralgia (23%), and diarrhea (21%). Importantly, 43% of patients 
enrolled had received previous chemotherapy in the neoadjuvant or adjuvant setting.  
 
In the PALOMA-3 study13 the toxicity profile was not different and neutropenia was the most 
common adverse event occurring in 78.8% of patients receiving palbociclib-fulvestrant (any 
grade). Grade 3/4 neutropenia occurred in 62% of patients in the palbociclib arm compared with 
0.6% in the placebo arm. In this study, low rates of neutropenia-related complications and  
 
 
febrile neutropenia were also confirmed and were reported in 0.6% of patients in each arm. 


13 
 
Remarkably, 31.6% of patients required dosage reduction of palbociclib.   
  
1.3. 
Minorities enrollment in clinical trials  
 
The National Institute of Health (NIH) guidelines on the inclusion of women and minorities in 
clinical trials published in 1994 and updated in 2001 called for the initiation of programs and 
support for outreach efforts to recruit underrepresented groups into clinical trials.14 Although 
these efforts have led to increased participation in some instances of previously excluded 
groups onto clinical trials, minority populations continue to be consistently underrepresented.  In 
addition there is a lack of appreciation of genetic factors particular to Asian, African-American, 
Hispanic, and other ethnic communities.15 This diversity gap can lead to sub-optimal 
development of new medicines, compromise the generalization of clinical trial results and further 
exacerbate minority health disparities.  
 
The ability to trust and apply the results of a clinical trial, as well as transfer them into clinical 
practice, is related to the type and number of patients enrolled in that trial. If trials do not include 
minorities, then there is a question of whether or not the results of the studies are relevant to 
everyone across the board. According to a 2011 report from the conference "Dialogues on 
Diversifying Clinical Trials," sponsored by the FDA, African Americans represent 12% of the 
U.S. population but only 5% of clinical trial participants and Hispanics make up 16% of the 
population but only 1% of clinical trial participants.  
  
1.4. 
Neutrophil count in African Americans   
 
Benign ethnic neutropenia (BEN) is a condition used to describe individuals with neutrophil 
counts less than 1.5x109cells/L in the absence of other causes.16 It is common in people of 
African ancestry, including African Americans, and identifies a group (estimated in 50% of 
African Americans) with low absolute neutrophil count (ANC) but no increased risk of 
agranulocytosis or infection. Published evidence implicates a polymorphism (SNP rs2814778 at 
chromosome 1q23.2) in the Duffy Antigen Receptor Chemokine (DARC) gene in the 
pathophysiology of BEN.17   
 
An ANC cutoff at 1.5x109 cells/L for trial enrollment for African American patients when many 
have ethnic neutropenia may not be necessary.18 Currently there are insufficient data to indicate 
that individuals with BEN would face a higher risk of febrile neutropenia greater than those 
without BEN. In a recent pilot study led by a group of investigators from the University of 
Maryland (not published yet), 12 African American patients with BEN and schizophrenia 
received clozapine (associated with neutropenia) safely and successfully continued despite low 
baseline ANC and outside current guidelines. In addition it has been reported that African 
American women with early breast cancer have lower white blood count (WBC) after 
chemotherapy and longer duration of treatment resulting in lower dose intensity of treatment 
which can contribute to observed racial differences in breast cancer survival. In this 
retrospective study there was no mention to an increased risk of febrile neutropenia in African 
American women compared to white.19   
 
African American women have been underrepresented in clinical trials with palbociclib. This 
may be partially explained by rigid requirements for minimal WBC numbers (absolute neutrophil 


14 
 
count of 1500/mm3 or higher). In the clinical trials where palbociclib was used for treatment of 
advanced breast cancer and have been published thus far, in PALOMA-1 there is no 
demographics available for the race/ethnicity of the participants, and in PALOMA-3 there is 
mention that 5.8% of patients enrolled in the experimental arm self-identified as black or other. 
Therefore conclusions regarding the rate of neutropenia and febrile neutropenia in African 
American patients treated with palbociclib cannot be safely extrapolated from the trials 
previously discussed.   
  
1.5. 
Metabolite and exosomal signature of endocrine resistance   
 
Metabolomics is a novel “omics” tool with promising clinical applications including breast 
cancer20. Onco-metabolites identified in blood, tissue or urine can be used as biomarkers of 
cancer21,22. While the metabolite signature of endocrine resistant breast cancer is not well 
understood, we have identified an increased dependence on glutamine metabolism in endocrine 
resistant breast cancer cell models23. Metabolic profile of serially collected blood samples have 
enabled detection of breast cancer relapse24. In this correlative study, untargeted metabolomics 
analysis of serum will allow identification of metabolite markers of endocrine resistance by 
comparing metabolite profile of responders to that of non-responders. Furthermore, clinical data 
such as diabetes, body mass index (BMI) or cardiovascular history will be helpful in stratifying 
our findings.     
  
In breast cancer, exosomes (30-120 nm structures that are derived from cell membranes) have 
been suggested as a means of cell-to-cell communication that can be deregulated25. Exosomes 
are present in most human body fluids, including blood plasma/serum, saliva, breast milk, 
cerebrospinal fluid, urine and semen). These vesicles contain multiple proteins, DNA, mRNA, 
miRNA, long non-coding RNA, and even genetic materials of viruses or prions26. 
Characterization of exosomes can be useful as predictive biomarker signatures of drug 
resistance in the clinic27,28. Preliminary studies in our laboratory show distinct contents in 
exosomes derived from endocrine sensitive versus resistant cells.   
  
1.6. 
Study Rationale  
 
The proposal of this study is to evaluate the hematological safety of palbociclib in combination 
with letrozole or fulvestrant in African American women with hormone receptor positive HER2 
negative advanced breast cancer. Currently there are insufficient data to describe the 
hematological safety for these individuals who have a high incidence of BEN.  
 
We propose to lower the ANC cutoff for the enrollment of African American patients to 
1000/mm3 or higher. The standard lower limit of ANC of 1500/mm3 for initiation of treatment in 
this population has been previously challenged by other authors.18,29 We will follow the 
recommended guidelines for management of neutropenia and dose adjustments. In addition we 
will do correlative studies looking at metabolite biomarkers and exosomal signature of endocrine 
resistance.    
  
2. STUDY OBJECTIVES AND ENDPOINTS  
  
2.1. Objectives  
  


15 
 
Primary Objective  
To evaluate the hematological safety of palbociclib with letrozole or fulvestrant in African 
American women with hormone receptor positive HER2 negative advanced breast cancer. Use 
of anastrozole or exemestane permitted in the event of letrozole intolerance.  
 
Hematological safety is defined as a composite endpoint of episodes of febrile neutropenia and 
treatment discontinuation due to neutropenia according to current recommendations for 
management of neutropenia.  
  
 Secondary Objectives  
  
1. To evaluate delays in palbociclib therapy attributed to neutropenia  
2. To evaluate dose reductions in palbociclib therapy attributed to neutropenia  
3. To evaluate grade 3/4 neutropenia  
4. To evaluate the efficacy of palbociclib with letrozole or fulvestrant in African American women 
with HR positive HER2 negative advanced breast cancer with evaluable disease.  Use of 
anastrozole or exemestane permitted in the event of letrozole intolerance.  
5. To describe metabolite and exosomal signature and evaluate correlations with disease 
response  
6. To describe baseline ANC prior to cancer diagnosis and the Duffy Null polymorphism (SNP 
rs2814778 at chromosome 1q23.2) and explore correlations with hematological safety   
   
2.2. Endpoints  
  
Primary Endpoint  
  
Proportion of patients who complete planned oncologic therapy without the development of a 
hematological event defined as episodes of febrile neutropenia and treatment discontinuation 
due to neutropenia according to current recommendations for management of neutropenia. 
 
If a patient comes off study prior to cycle 1 day 14, that patient will be replaced. 
  
There are different definitions of febrile neutropenia but for study purpose this will be defined 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0: “ANC less than 1000/mm3 with a single temperature of >38.3 degrees 
Celsius (101 degrees Fahrenheit) or a sustained temperature of 38 degrees Celsius (100.4 
degrees Fahrenheit) for more than one hour.”  
  
Planned oncology therapy is defined as completion of one year of therapy for advanced breast 
cancer in the absence of disease progression or cessation of study drug due to progressive 
disease or non-hematological toxicity.  
  
Secondary Endpoints  
  
1. Number of patients who required dose delays in palbociclib attributed to neutropenia.  
2. Number of patients who required dose reductions in palbociclib therapy attributed to 
neutropenia  
3. Rate of grade 3/4 neutropenia  


16 
 
4. Clinical Benefit Rate (CBR), for those with evaluable disease, defined as the percentage of 
patients who achieved complete response, partial response and stable disease at 24 weeks  
5. To evaluate correlations between metabolite and exosomal signature with disease response  
6. To evaluate correlations between baseline ANC prior to cancer diagnosis and the Duffy Null 
polymorphism (SNP rs2814778 at chromosome 1q23.2) with hematological safety   
 3. STUDY DESIGN  
  
Figure 1. Study design  
  
 
 
  
  
This is a phase II, single arm, multicenter clinical trial.  
  
Eligible patients will be self-identified Black, African or African American women with HR 
positive and HER2 negative advanced breast cancer. Patients will have histologically or 
cytologically proven diagnosis of adenocarcinoma of the breast (locoregionally recurrent or 
metastatic disease) and will be candidates to receive letrozole or fulvestrant for their advanced 
disease. Use of anastrozole or exemestane permitted in the event of letrozole intolerance.  
 
Patients will be enrolled and will continue to receive treatment with palbociclib until disease 
progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, 
or completing 12 months on study, whichever occurs first. If a patient comes off study because 
she completed 12 months of palbociclib/letrozole or fulvestrant on study she can continue 
commercial drugs at the treating physician’s discretion.  Use of anastrozole or exemestane 
permitted in the event of letrozole intolerance.  
  
  
Patients will undergo adverse events (AE) monitoring as per local practice. Adverse events will 


17 
 
be characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), and 
seriousness. All grades, all causality AEs and all serious adverse events (SAEs) will be 
recorded in the case report forms (CRF). All deaths occurring up to 28 days after palbociclib is 
discontinued will be recorded.  
  
Hematology laboratory data will be recorded every 2 weeks for the first 2 cycles of therapy, then 
monthly at the start of each cycle thereafter. Recommendation for monitoring neutropenia 
available in the label and dose modification tables will be followed. Retreatment criteria are 
based on time to recovery of neutrophil count. The clinical actions taken as a result of Grade 3 
neutropenia, including the use of G-CSF, if any, will be recorded.  
  
Tumor response will be assessed as per local practice and only investigator tumor assessments 
will be collected for those who have evaluable disease. The date of tumor progression will be 
recorded.  
   
3.1 Duration of therapy  
  
Treatment will continue until participation and study therapy is no longer in the patient’s best 
interest. Reasons for withdrawing a patient include, but are not limited to:  
- Disease progression  
- The occurrence of an adverse event or a concurrent illness. Patients removed from study for 
unacceptable treatment related adverse event(s) will be followed until resolution or stabilization 
of all treatment related adverse events to Grade 2 or lower.   
- A patient’s request to end participation  
- A patient’s non-compliance or simply significant uncertainty on the part of the Investigator that 
continued participation is prudent.  
 
  
Patients will be followed on study for a maximum of 12 months. If there are no reasons for 
withdrawing a patient at 12 months, patient can continue off study on the same therapy at the 
physician’s discretion.   
  
4. PATIENT SELECTION  
  
4.1. Inclusion Criteria  
  
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.  
  
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:  
  
1. Self-identified Black, African or African American women of ≥ 18 years of age with 
proven diagnosis of advanced breast cancer (locoregionally recurrent or metastatic 
disease), either from the primary or a metastatic site.  
 
2. Post-menopausal status defined by: a) age ≥60 years; b) age <60 years and cessation 
of regular menses for at least 12 consecutive months with no alternative pathological or 


18 
 
physiological cause; c) documented bilateral oophorectomy; d) medically confirmed 
ovarian failure  OR   
a. pre/peri-menopausal, ie, not meeting the criteria for being postmenopausal who 
are also receiving ongoing treatment with LHRH agonists (goserelin or 
leuprolide); the first injection should occur at least two weeks before study start.   
 
3. ER-positive and/or PR-positive tumor (≥1% positive stained cells) based on local 
laboratory results  
 
4. HER2-negative breast cancer based on local laboratory results (test to be used as per 
local practice). HER2-negative tumor is determined as immunohistochemistry score 0/1+ 
or negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17 ratio 
<2 or for single probe assessment a HER2 copy number <4.  
 
5. Patients must be appropriate candidates for letrozole therapy in any line of therapy or for 
fulvestrant for second line of therapy or beyond.  Use of anastrozole or exemestane 
permitted in the event of letrozole intolerance.   
 
6. Must have received no more than 2 lines of chemotherapy for the treatment of breast 
cancer, and one for the treatment of advanced breast cancer.  
 
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 (Appendix 
1)  
 
8. Adequate bone marrow function:  
a. Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 (1.0 x 109 /L);  
b. Platelets ≥100,000/mm3 (100 x 109 /L);  
c. Hemoglobin ≥9 g/dL (90 g/L).  
 
9. Adequate liver function  
 
- AST and/or ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);  
- Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone or liver metastases present);  
- Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert’s disease).  
 
10. Adequate renal function  
- Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min.  
 
11. Resolution of all acute toxic effects of prior therapy, including radiotherapy to grade ≤1 
(except toxicities not considered a safety risk for the patient) and recovery from surgical 
procedures.  
 
12. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study.  
 
13. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.  


19 
 
  
4.2. Exclusion Criteria  
  
Patients presenting with any of the following will not be included in the study:  
  
1. Current use of food or drugs known to be potent inhibitors or inducers of CYP3A4  
 
2. Known hypersensitivity to letrozole, anastrozole, exemestane, or fulvestrant, or any of its 
excipients, or to any palbociclib excipients. If hypersensitivity to letrozole, anastrozole, 
exemestane, or fulvestrant, patients will be allowed to go on study as long as they don’t 
have hypersensitivity to the endocrine therapy they will receive.   
 
3. Active uncontrolled or symptomatic brain metastases. Previously treated and clinically 
stable, as per Investigator’s judgment, brain metastases are permitted.  
 
4. Previous CDK4/6 inhibitor  
 
5. Other severe acute or chronic medical or psychiatric condition, including recent or active 
suicidal ideation or behavior, or laboratory abnormality that may increase the risk 
associated with study participation or investigational product administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator, 
would make the patient inappropriate for entry into this study.  
 
6. Pregnant or lactating patients. Patients of childbearing potential must agree to avoid 
pregnancy during study treatment and for at least two weeks after the last dose of the 
study drug.   
  
  
5. STUDY TREATMENTS  
  
5.1. Allocation to Treatment  
  
Following full assessment and determination that the patient meets all eligibility criteria and has 
given informed consent for study participation, the investigator or designee will contact the study 
principal investigator (PI) or designee and request study enrollment. A patient identification 
number will be assigned, which must be used on all CRF pages and on all documentation and 
correspondence referencing that patient.  
  
5.2. Compliance  
  
Patients will be required to return all bottles of palbociclib at the beginning of each clinical visit 
for drug accountability.  
 
Drug accountability will be performed at every clinical visit prior to dispensing drug supply for the 
next cycle(s). The number of remaining capsules will be documented and recorded to assess 
compliance.  
  
5.3. Drug Supplies  


20 
 
  
The investigational drug used in the course of this trial is palbociclib (IBRANCE®).  
  
5.3.1. Dosage Form(s) and Packaging  
  
5.3.1.1. Palbociclib  
  
Palbociclib will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of 
palbociclib free base. The oral drug formulation will be supplied in High Density Polyethylene 
(HDPE) bottles containing 75 mg, 100 mg, or 125 mg capsules.    
  
5.3.1.2. Letrozole  
  
Commercially available letrozole will be used. Locally obtained commercial supplies of letrozole 
will be used in accordance with local regulations.  
  
5.3.1.3. Fulvestrant  
  
Commercially available fulvestrant will be used. Locally obtained commercial supplies of 
fulvestrant will be used in accordance with local regulations. 
 
5.3.1.4 Anastrozole 
 
Commerically available anastrozole will be used. Locally obtained commercial supplies of 
anastrozole will be used in accordance with local regulations. 
 
5.3.1.5 Exemestane 
 
Commercially available exemestane will be used. Locally obtained commercial supplies of 
exemestane will be used in accordance with local regulations. 
  
 5.3.2. Preparation and Dispensing - Palbociclib  
  
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 clinical visit. Bottles contain 21 
capsules. 
  
Unused drug and/or empty bottles should be returned to the site at the next clinical visit. Unused 
returned medication MUST NOT be re-dispensed to patients.  
  
Palbociclib is an agent that must be handled and administered with care.  Patients should be 
instructed to keep their medication in the bottles provided and not transfer it to any other 
container. 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.  


21 
 
  
Only a single capsule strength will be dispensed to the patient at each dispensing visit.  
  
In the event of dose modification, request should be made of the patient to return all previously 
dispensed medication to the clinic and new capsules will be dispensed.  
  
  
5.3.3. Administration  
  
5.3.3.1. Palbociclib  
  
Palbociclib will be administered orally once a day at 125 mg/day for 21 days followed by 7 days 
off treatment for each 28-day cycle (Schedule 3/1). For patients enrolled with baseline ANC 
between 1000 and 1499/uL, initial dose of palbociclib will be 100mg once daily for 21days 
followed by 7 days off treatment. If no grade 3 or 4 neutropenia is observed in the two first 
cycles, dose will be increased to 125 mg/day on the third cycle and then follow general dose 
modifications.   
  
General rules for palbociclib administration:  
- 
Palbociclib should be taken with food.  
- 
Palbociclib capsules should be swallowed whole (do NOT chew, crush or open them prior to   
swallowing).  
- 
No capsule should be ingested if it is broken, cracked, or otherwise not intact  
- 
Patients should be encouraged to take their dose at approximately the same time each day.  
- 
Patients who miss a day’s dose entirely must be instructed NOT to “make it up” the next 
day.  
- 
Patients who vomit any time after taking a dose must be instructed NOT to “make it up,” and 
to resume treatment the next day as prescribed.  
- 
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the next 
day’s dose. Also refer to the Medication Errors (Section 8.3.1) for further details on 
medication errors and overdose.  
 
 5.3.3.2. Letrozole  
  
Letrozole will be administered orally at 2.5 mg once daily as continuous daily dosing schedule 
according to product labeling and in compliance with its local prescribing information.   
  
5.3.3.3. Fulvestrant   
  
Fulvestrant will be administered as intramuscular injections at the initial dose of 500 mg on days 
1, 15, and 29, and as maintenance dose of 500 mg once every 28 days, according to product 
labeling and in compliance with its local prescribing information.   
 
5.3.3.4. Anastrozole 
 
Anastrozole will be administered orally at 1mg once daily as continuous daily dosing schedule 
according to product labeling and in compliance with its local prescribing information. 


22 
 
 
5.3.3.5. Exemestane 
 
Exemestance will be administered orally at 25mg once daily as continuous daily dosing 
schedule according to product labeling and in compliance with its local prescribing information. 
  
5.3.4. Recommended Dose Modification  
  
In the event of significant treatment-related toxicity, administration of palbociclib may need to be 
adjusted as described in the following sections.  As letrozole, anastrozole, exemestane, and 
fulvestrant doses cannot be reduced, letrozole, anastrozole, exemestane, or fulvestrant 
treatment may be interrupted in the case of toxicity as described below.  
  
Depending on the nature of the toxicity observed, treatment interruption may be required for one 
or both study drugs in the combination. In the event treatment interruption is deemed necessary 
for just one of the study drugs in the combination, treatment with the other drug may continue as 
planned if deemed clinically appropriate.  
  
In case of palbociclib dose delays, administration of letrozole, anastrozole, exemestane, or 
fulvestrant may continue according to the pre-planned schedule.  
  
In case of palbociclib permanent discontinuation, the patient will undergo End of Study visits as 
described in Schedule of Activities (Table 5). Continuation of letrozole, anastrozole, 
exemestane, or fulvestrant would be off study per treating physician discretion.  
  
 5.3.4.1. Dosing Interruptions/Delays – Recommendations for Palbociclib  
  
Patients experiencing the following adverse events may have their treatment with palbociclib 
interrupted/delayed until criteria for retreatment are met (Section 5.3.4.2).  
  
Patients should not hold or discontinue palbociclib for non-hematological side effects potentially 
or likely related to concomitant letrozole, anastrozole, exemestane, or fulvestrant therapy (eg, 
Grade 3 or long lasting Grade 2 joint pain) as per the investigator’s judgment.  
  
Depending on when the AE resolves, a treatment interruption may lead to the patient missing all 
subsequent planned doses within that same cycle or even to delay in the initiation of the 
subsequent cycle.  
  
Doses omitted for toxicity are not replaced within the same cycle.  
  
Doses should be held until toxicity resolution as per Retreatment Criteria (Section 5.3.4.2).  
  
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in the Dose Reductions (Section 5.3.4.3).  
  
In the case of Grade 3 neutropenia, consider repeating complete blood count (CBC) monitoring 
within one week in accordance with best local practice and report in the CRF in order to 


23 
 
document the level of neutropenia and the time to recovery of neutrophils to ≥1,000 cells/mm3. 
Retreatment criteria are based on time to recovery of neutrophil count. For patients who develop 
Grade 3 or 4 neutropenia, refer to the dose modification tables. The clinical actions taken as a 
result of Grade 3 neutropenia, including the use of G-CSF, if any, will be recorded.  
  
If a dose reduction is applied in the same cycle, the patient will need to return to the clinic to 
receive new drug supply.  
  
 
 
5.3.4.2. Retreatment Criteria - Palbociclib  
  
Retreatment with palbociclib following treatment interruption for treatment related toxicity may 
not occur until all of the following parameters have been met.  
- 
Platelet count ≥ 50,000/mm3  
- 
ANC ≥1000/mm3 and no fever  
- 
Grade ≥3 non-hematologic AEs (including nausea, vomiting, diarrhea, and hypertension 
only if persisting despite optimal medical management) have recovered to grade≤1 or baseline 
or, at the investigator discretion, grade≤2 if not considered a safety risk for the patient  
  
If a treatment delay results from decline in hematologic parameters, the frequency of blood 
count assessments should be increased as per best clinical practice.  
  
If the retreatment parameters are met within 3 weeks of dose interruption, palbociclib may be 
resumed at the same dose.  
  
If the retreatment parameters have not been met after > 3 weeks of dose interruption, the 
patient should permanently discontinue palbociclib treatment. However, if a patient is deemed to 
be suitable for a lower dose of palbociclib, treatment may be resumed at a lower dose at the 
investigator’s discretion (see below for suggested dose adjustments).  
   
5.3.4.3. Dose Reductions - Palbociclib  
Following dose interruption or cycle delay the palbociclib, dose may need to be reduced when 
treatment is resumed.  Available dose levels in case of palbociclib dose reduction are reported 
in Table 2.  
 
Table 2. Available dose levels  
Recommended Dose Modification for Adverse Reactions Dose Level  Dose   
Recommended starting dose   
125 mg/day  
First dose reduction   
100 mg/day  
Second dose reduction   
75 mg/day*   
 
*If further dose reduction below 75 mg/day is required, discontinue the treatment.  
  
Once a dose has been reduced, all subsequent cycles should be administered at that 
dose level, unless further dose reduction is required.  Dose re-escalation is not allowed.  


24 
 
  
No specific dose adjustments are recommended for grade 1/2 treatment related toxicity. 
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.  
  
All dose modifications/adjustments must be clearly documented in the CRF along with 
reasons for dose modification/adjustment.  
Palbociclib recommended dose modifications for treatment related toxicities requiring 
treatment interruption/delay or persisting despite optimal medical treatment are 
described in Table 3 and 4.  
 
Table 3. Dose modification and management for hematologic toxicities  
CTCAE grade  
Dose Modifications  
Grade 1 or 2   
No dose adjustment is required.   
Grade 3 neutropenia (ANC<1000/mm3),  
thrombocytopenia (PLC < 50,000/mm3) or 
anemia (Hgb < 8g/dL)  
  
No dose adjustment is required. Consider 
repeating CBC monitoring one week later. 
Withhold initiation of next cycle until recovery 
to Grade ≤2.   
Grade 3 neutropenia (<1000 to 500/mm3) + 
fever ≥38.5ºC and/or infection   
Withhold palbociclib and initiation of next cycle 
until recovery to Grade ≤2 (≥1000/mm3). 
Resume at next lower dose.   
Grade 4 neutropenia (ANC<500/mm3), 
thrombocytopenia (PLC < 25,000/mm3) or 
anemia (life threatening consequences)   
Withhold palbociclib and initiation of next cycle 
until recovery to Grade ≤2. Resume at next 
lower dose.   
  
Table 4. Dose Modification and Management – Non-Hematologic Toxicities  
CTCAE Grade   
Dose Modifications   
Grade 1 or 2   
No dose adjustment is required.   
Grade ≥3 non-hematologic toxicity (if persisting 
despite medical treatment)   
Withhold until symptoms resolve to:   
• Grade ≤1;   
• Grade ≤2 (if not considered a safety 
risk for the patient)   
Resume at the next lower dose.   
 
 5.4. Drug Storage  
  
Palbociclib, letrozole, anastrozole, exemestane, and fulvestrant should be stored in 
original containers and in accordance with the FDA approved drug label.  
  
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products 
are stored in a secured area with controlled access under recommended storage 


25 
 
conditions and in accordance with applicable regulatory requirements.  
  
Any excursions from the product label storage conditions should be reported upon 
discovery. The site should actively pursue options for returning the product to labeled 
storage conditions, as soon as possible. Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  
  
Once an excursion is identified, the investigational product must be quarantined and not 
used until the sponsor provides documentation of permission to use the investigational 
product. Specific details regarding information the site should report for each excursion 
will be provided to the site.  
  
Site staff will instruct patients on the storage requirements for take home medications 
including how to report temperature excursions.  
  
5.5. Drug Accountability  
  
The investigator’s site must maintain adequate records documenting the receipt, use, 
loss, or other disposition of palbociclib drug supply. Patients will be required to return all 
bottles of palbociclib at the beginning of each clinical visit for drug accountability (see 
also Section 5.2 Compliance).  
  
The sponsor or designee will provide guidance on the destruction of unused 
investigational product (eg, at the site).  
  
The site will be responsible for drug destruction. The investigators must ensure that the 
drug is destroyed in compliance with applicable environmental regulations, and 
according to their approved institutional practices. All destruction must be adequately 
documented.  
  
5.6. Concomitant Medication(s)  
  
Patients must be instructed not to take any additional medications (over-the-counter or 
other products) during the study without prior consultation with the investigator.  
  
All concomitant medications required to clinically manage patients while they are 
receiving palbociclib therapy are permitted unless specified below in Sections 5.6.1 and 
5.6.2. Documentation of these medications will not be collected on the CRF but will 
need to be available from the patient’s medical record upon request by the Sponsor.  
  
An exception will be the use of growth factors including granulocyte colony stimulating 
factor (GCSF). Growth factors should not be used for upfront prophylaxis, but may be 
used to treat neutropenia associated with clinically significant complications, and should 
follow established ASCO guidelines. Use outside this indication should be discussed 


26 
 
with the study PI. Dose reduction is the preferred initial method to address neutropenia 
rather than GCSF. GCSF use will be documented in the CRF as well as other agents 
used to treat/manage AEs while on therapy.  
  
Immunizations (inactivated vaccines, including inactivated influenza vaccine) prior to 
initiation of therapy will be administered as clinically indicated and documented in CRF.   
  
Proton pump inhibitors (PPI): In a drug interaction trial in healthy subjects, coadministration of a  
single 125 mg dose of palbociclib with multiple doses of the PPI rabeprazole under fed 
conditions decreased palbociclib Cmax by 41%, but had limited impact on AUC inferior (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. In another healthy subject study, 
coadministration of a single dose of palbociclib with multiple doses of the PPI rabeprazole under 
fasted conditions decreased palbociclib AUC inf and Cmax by 62% and 80%, respectively, 
when compared to a single dose of palbociclib administered alone.   
  
Surgery is allowed during protocol therapy, however it is suggested to avoid nadir of counts at 
time of surgery. Patients pursuing surgery must hold palbociclib therapy 7 days before the 
surgery and up to 3 weeks after surgery. Patients may resume palbociclib therapy once 
satisfactory wound healing and recovery have occurred. Patients should continue endocrine 
therapy if palbociclib is held for surgery.  
  
  
5.6.1. Prohibited Medications  
  
Anticancer agents: No additional investigational or commercial anticancer agents such as 
chemotherapy, immunotherapy, targeted therapy, biological response modifiers, or endocrine 
therapy other than letrozole, anastrozole, exemestane, or fulvestrant will be permitted during the 
study.  
  
Strong CYP3A inhibitors/inducers: palbociclib is metabolized to multiple metabolites in a 
qualitatively similar manner in rat, dog and human liver microsomes.  In vitro, palbociclib is 
primarily metabolized by CYP3A4 enzymes.  Co-administration with drugs that are strong 
CYP3A inhibitors and inducers may change the plasma concentrations of palbociclib in humans.  
  
The concurrent use of strong CYP3A inhibitors, including amprenavir, atazanavir, boceprevir, 
clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and 
grapefruit, grapefruit juice or any product containing grapefruit, are not allowed in the study.  
  
The concurrent use of strong CYP3A inducers, including carbamazepine, felbamate, 
nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s 
wort, are not allowed in the study.  


27 
 
  
5.6.2. Medications Not Recommended  
 
Alternative therapies should be considered whenever possible for the following treatments:  
  
CYP3A Substrates: caution must be exercised in patients receiving palbociclib in combination 
with drugs that are predominantly metabolized by CYP3A.  In particular, co-administration of  
 
palbociclib with CYP3A4 substrates with narrow therapeutic index including, but not limited to 
alfentanil, aripiprazole, cyclosporine, ergotamine, fentanyl, halofantrine, pimozide, quinidine, 
sirolimus, tacrolimus, triazolam are not recommended during the treatment with palbociclib.  
  
The use of herbal medicines is not recommended.  
  
6. STUDY PROCEDURES  
 
6.1. Schedule of events   
Study procedure/ 
assessment 
Screening 
Treatment:  one cycle =28 days 
End of 
Treatmentc 
End of 
Studyc 
Cycles 1 and 2 
Cycles ≥ 3 
Study day 
Within 28 days prior 
to study entry 
Day 1 
Day 14 
 
 
 
Time Window 
+/- 2 days 
+/- 2  days 
+/- 2 days 
+/- 7 days 
+/- 7 
days 
Procedures at screeninga 
Informed Consentd 
X 
 
 
 
 
 
Eligibility criteria 
checkliste 
X 
 
 
 
 
 
Registrationf 
X 
 
 
 
 
 
Medical Historyg 
X 
 
 
 
 
 
CBC with diff prior 
to cancer diagnosis 
(if available)s 
 
X 
 
 
 
 
 
Procedures at screening and on study 
Physical 
examination/ 
Clinical Visitsb 
 
X 
 
Per routine clinical practice 
 
Comorbidities 
(including DM and 
CVD)h 
X 
 
Per routine clinical practice 
 
ECOG PSi 
X 
Per routine clinical practice 
X 
 
BMI 
X 
Per routine clinical practice 
X 
 
Concomitant Meds 
Review 
X 
X 
 
X 
X 
 
Adverse Eventsj 
X 
X 
X 
X 
X 
X 
Medication Diaryk 
 
X 
 
X 
X 
 
Treatments 
Palbociclibl 
 
Orally once daily from D1 to D21 of 
each cycle (schedule 3/1) 
 
 
Letrozolem 
 
or 
 
Orally once daily (schedule continuous 
dosing) 
Or 
 
 


28 
 
 
Fulvestrantt 
500mg intramuscular injection on days 
1, 15, and 29, and 500mg once every 
28 days thereafterc 
Laboratory tests/ Imaging/ Correlative Blood Studies 
Tumor assessmentn 
X 
Per routine clinical practice 
 
Hematology (CBC 
with diff)o 
X 
X 
X 
X 
X 
X 
Chemistryp 
X 
Per routine clinical practice 
 
Pregnancy testq 
X 
 
 
 
 
 
Research labsr 
 
X 
X 
X 
X 
X 
 
Footnotes to the schedule of activities:  
aScreening: All assessments should be performed within 28 days prior to study entry.  
bClinical Visits: clinical visits will be conducted as per local practice and as clinically indicated. Physical 
Examination includes general clinical examination of major body systems.   
cEnd of Study: The End of Treatment visit will be conducted when palbociclib is permanently 
discontinued for any reason. The indicated assessments are to be obtained if not completed in the last 
week of therapy. The End of Study visit will occur 28 days after last dose of palbociclib or after patient 
comes off study, whichever comes last. End of Study visit will be completed also in case a patient will 
continue on commercial palbociclib. Adverse events should be followed up until all serious or study drug-
related toxicities have resolved or are determined to be “chronic” or “stable”.  
dInformed Consent: Must be obtained prior to undergoing any study specific procedures.  
eEligibility Criteria Evaluation: Patients must meet all of the eligibility criteria reported in the protocol 
and checklist must be filled.  
fRegistration: Patient identification number will be attributed to each patient.  
gMedical History: Medical history includes history of disease process other than oncology (active or 
resolved). It should also include Oncological history with date of primary diagnosis, information on prior 
anti-tumor treatments and radiotherapy, and oncologic surgeries.  
hComorbidities including diabetes mellitus (DM) and cardiovascular disease (CVD) should be 
documented as screening and as clinically indicated. This should be part of the clinical visits.  
iECOG Performance Status: To be performed at Screening, as per routine clinical practice during the 
treatment, and at the end of treatment. ECOG performance scale is available in Protocol Appendix 1.  
jAdverse Events: Patients must be followed for Adverse Events (AEs) from the time they signed the 
informed consent until 28 days after the last treatment administration or until all palbociclib-related 
toxicities have resolved, whichever is later. AEs (serious and non serious) should be recorded on the 
CRF from the time the patient has taken at least one dose of study treatment through last patient visit. 
AEs should be documented and recorded at each clinical visit using NCI CTC-AE version 4.03 from the 
time the patient has taken at least one dose of study treatment through last patient visit. For SAEs, the 
active reporting period to Pfizer or its designated representative begins from the time that the patient 
provides informed consent through and including 28 calendar days after the last administration of the 
investigational product. SAEs experienced by a patient after the active reporting period has ended should 
be reported to the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to study drug are to be 
reported to the Sponsor.  
kPatient Medication Diary: patient will receive a new medication diary on day 1 of each cycle of and will 
return it filled and signed at the end of each cycle  
lPalbociclib Administration: Palbociclib will be administered orally once daily at the starting dose of 125 
mg, on Day 1 to Day 21 followed by 7 days off treatment (Schedule 3/1). The patient will receive drug 
supply at the clinical site that will be sufficient for 1-3 months of treatment depending on the decision of 
the treating physician.  
mLetrozole, Anastrozole, and Exemestane Administration: Letrozole will be administered orally once 


29 
 
daily at the dose of 2.5 mg (continuous daily dosing schedule).  Anastrozole will be administered orally 
once daily at the dose of 1mg (continuous daily dosing schedule).  Exemestane will be administered 
orally once daily at the dose of 25mg.  Locally obtained supplies of letrozole, anastrozole, and 
exemestane will be used. 
nTumor Assessments: Tumor assessments are to be performed at Screening and as per local practice 
and according to the patient’s clinical status thereafter. Tumor assessment evaluation will be conducted 
as per local guidelines. Only investigators’ assessments will be recorded in the CRF.  
oHematology: To include complete blood count (CBC) with differential. To be performed to check 
patient’s eligibility at Screening, every 2 weeks (Days 1 and 14) of the first 2 cycles, then monthly on Day 
1 of each subsequent cycle of treatment with palbociclib and at the end of treatment. In the case of Grade 
3 neutropenia consider repeating complete blood count monitoring one week later in accordance with 
best local practice and report in the CRF in order to document the ANC value at the time of severe 
neutropenia as well as the time to recovery of neutrophils to ≥1,000 cells/mm3. Retreatment criteria are 
based on time to recovery of neutrophil count. For patients who develop Grade 3 or 4 neutropenia, refer 
to the dose modification tables. If granulocyte-colony stimulating factors (G-CSF) and/or antibiotics are 
administered, their use will be documented on the CRF.  For patients who experience a maximum of 
Grade 1 or 2 neutropenia in the first 6 cycles, complete blood counts for subsequent cycles may be 
performed every 3 months only, prior to the beginning of a cycle and as clinically indicated.   
pBlood Chemistry: To be performed to check patient’s eligibility at Screening, and as per routine clinical 
practice thereafter. Only laboratory data at Screening will be recorded on the CRF.  
qPregnancy Test (serum or urine): Required for women of childbearing potential  
rResearch labs: refer to Study Procedures Manual for collection, labeling, processing and shipping 
instructions.  
sCBC with diff prior to cancer diagnosis: this information will be collected if available   
tFulvestrant administration: will be administered as intramuscular injections at the initial dose of 500 mg 
on days 1, 15, and 29, and as maintenance dose of 500 mg once every 28 days. Locally obtained 
commercial supplies of fulvestrant will be used.    
   
6.2. Patient Withdrawal  
  
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or Sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol required schedule of study 
visits or procedures at a given study site.  
  
Reasons why patients may discontinue or be withdrawn from the protocol may be due to the 
following:  
- Adverse events  
- Intercurrent illness  
- Disease progression  
- Patient is non-compliant  
- Patient is lost to follow-up  
- Withdrawal of consent  
  
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. In any circumstance, every effort should be made to document patient outcome, if 
possible. The investigator should inquire about the reason for withdrawal, request the patient to 
return all unused investigational product, request the patient to return for a final visit, if 
applicable, and follow up with the patient regarding any unresolved AEs.  


30 
 
  
 7. ASSESSMENTS  
  
7.1. Safety Assessments  
  
Safety assessment will consist of monitoring of all adverse events (AEs), including serious 
adverse events (SAEs) at every clinical visit and monitoring of hematology to be performed to 
check patient’s eligibility at Screening, every 2 weeks (Days 1 and 14) of the first 2 cycles, then 
monthly on Day 1 of each subsequent cycle of treatment with palbociclib and at the end of 
treatment. In the case of Grade 3 neutropenia consider repeating complete blood count 
monitoring within one week in accordance with best local practice and report in the CRF in order 
to document the ANC value at the time of severe neutropenia as well as the time to recovery of 
neutrophils to ≥1,000 cells/mm3.  Retreatment criteria are based on time to recovery of 
neutrophil count. For patients who develop Grade 3 or 4 neutropenia, refer to the dose 
modification tables.  
  
Other procedures as necessary according to standard of care and in accordance with each 
site’s institutional guidelines will be assessed to monitor for adverse events related to the 
underlying disease, treatment with palbociclib or treatment with letrozole, anastrozole, 
exemestane, or fulvestrant or supportive therapies (see Section 8 for Adverse Event Reporting).  
  
Information generated from these assessments may also be used to determine if an adverse 
event occurred as defined in Section 8.  
  
 7.1.1. Physical Examination  
  
A full physical examination of all major body systems will be required at Screening. Symptom 
directed physical examinations will be performed as per routine clinical practice during the 
study.  Only physical examination at Screening will be recorded on the CRF. Physical 
examinations performed during treatment will need to be available from the patient’s medical 
record upon request by the Sponsor.  
  
The Eastern Cooperative Oncology Group (ECOG) performance status (PS) scale will be 
required at Screening, as per routine clinical practice during the study, and at the end of 
treatment. Data collected at Screening and at the end of treatment will be recorded on the CRF.  
Other ECOG PS assessments during study will need to be available from the patient’s medical 
record upon request by the Sponsor.  ECOG PS scale is available in Protocol Appendix 1.  
   
7.1.2. Laboratory Safety Assessments  
  
Blood tests will include the following:  
 
1. Hematology panel: complete blood count with differential  
2. Blood chemistry panel: ALT, ASL, alkaline phosphatase, total bilirubin, serum creatinine  
 
Blood tests will be drawn at the time points described in Table 5 (Schedule of Activities) and 
analyzed at local laboratories.  
  


31 
 
Hematology panel (includes complete blood count with differential) will be performed to verify 
patient’s eligibility at Screening, every 2 weeks (Days 1 and 14) of the first 2 cycles of therapy, 
then monthly on Day 1 of each subsequent cycle of treatment with palbociclib and at the end of 
treatment.  Laboratory data will be recorded on the CRF.  
  
In the case of Grade 3 neutropenia, consider repeating complete blood count monitoring within 
one week in accordance with best local practice and report in the CRF in order to document the 
level of neutropenia and the time to recovery of neutrophils to ≥1,000 cells/mm3. Retreatment 
criteria are based on time to recovery of neutrophil count. For patients who develop Grade 3 or 
4 neutropenia, refer to the dose modification tables. The clinical actions taken as a result of 
Grade 3 neutropenia, including the use of G-CSF, if any, should be recorded.  
  
Blood Chemistry will be performed to verify patient’s eligibility at Screening, and as per routine 
clinical practice thereafter. Only laboratory data at Screening will be recorded on the CRF.  
During the study blood chemistry data will not be collected on the CRF but will need to be 
available from the patient’s medical record upon request by the Sponsor. In the case a 
laboratory abnormality meets the definition of AE, as determined by the investigator and 
according to Adverse Event Reporting Section 8, this must be captured on an AE CRF page.  
  
7.2. Tumor Assessments  
  
Tumor assessments are to be performed at Screening and as per routine clinical practice and 
according to the patient’s clinical status thereafter (see also Schedule of Activities, Table 5). 
Tumor assessment evaluation will be conducted as per local practice at each institution.   
  
Only investigators’ assessments will be recorded in the CRF.  
  
 8. ADVERSE EVENT REPORTING  
  
8.1. Adverse Events  
  
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections.  
  
For all AEs, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, sufficient 
information should be obtained by the investigator to determine the causality of the AE. The 
investigator is required to assess causality. Follow-up by the investigator may be  
 
 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.  
  
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.  


32 
 
  
 8.2. Reporting Period  
  
For SAEs, the active reporting period to Pfizer or its designated representative begins from the 
time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including 28 calendar days after the last administration of 
the investigational product. Serious adverse events occurring to a patient after the active 
reporting period has ended should be reported to the Sponsor if the investigator becomes aware 
of them; at a minimum, all serious adverse events that the investigator believes have at least a 
reasonable possibility of being related to study drug are to be reported to the Sponsor.  
  
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least one dose of palbociclib through last patient visit.  
  
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs ends 
at the time the new treatment is started.  Death must be reported if it occurs during the SAE 
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment.  
   
8.3. Definition of an Adverse Event  
  
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
- Abnormal test findings (see section 8.4)  
- Clinically significant symptoms and signs  
- Changes in physical examination findings  
- Hypersensitivity  
- Drug abuse  
- Drug dependency  
 
 Additionally, they may include the signs and symptoms resulting from:  
- Drug overdose  
- Drug withdrawal  
- Drug misuse  
 
- Drug interactions  
- Extravasation  
- Exposure during pregnancy  
- Exposure via breast feeding  
- Medication error  
- Occupation exposure  
- Worsening of signs and symptoms of the malignancy under study should be reported as AEs 
in the appropriate section in the CRF  
  
Disease progression assessed by measurement of malignant lesions on radiographs or other 
methods should not be reported as AEs.  


33 
 
  
 8.3.1. 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 should be notified 
immediately.  
  
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.  
   
8.4. Abnormal Test Findings  
  
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  
- Test result leads to a change in study dosing (outside of protocol-stipulated dose adjustments) 
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  
  
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.  
   
8.5. Serious Adverse Events  
  
An SAE is any untoward medical occurrence at any dose that:  
- Results in death;  
- Is life-threatening (immediate risk of death);  
- Requires inpatient hospitalization or prolongation of existing hospitalization;  
- Results in persistent or significant disability/incapacity (substantial disruption of the ability to 
conduct normal life functions);  
- Results in congenital anomaly/birth defect  
  


34 
 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the safety reporting period.  
Hospitalization due to signs and symptoms of disease progression should not be reported as an 
SAE. If the malignancy has a fatal outcome during the study or within the safety reporting 
period, then the event leading to death must be recorded as an AE and as an SAE with CTC 
Grade 5 (see Section on Severity Assessment).  
  
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the patient 
or may require intervention to prevent one of the other AE outcomes, the important medical 
event should be reported as serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse.  
 8.5.1. Protocol-Specified Serious Adverse Events  
  
There are no protocol-specified SAEs in this study. All SAEs will be reported by the investigator 
as described in previous sections, and will be handled as SAEs in the safety database (see 
Section on SAE Reporting Requirements).  
   
8.6. Hospitalization  
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric wing  
to a medical floor, medical floor to a coronary care unit, or neurological floor to a tuberculosis 
unit).  An emergency room visit does not necessarily constitute a hospitalization; however, the 
event leading to the emergency room visit should be assessed for medical importance.  
  
Hospitalization does not include the following:  
- Rehabilitation facilities  
- Hospice facilities  
- Respite care (eg caregiver relif)  
- Skilled nursing facilities  
- Nursing homes  
- Same day surgeries  
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE. Examples include:  
- Admission for treatment of a preexisting condition not associated with the development of a 
new AE or with a worsening of the preexisting condition (eg, for work-up of persistent pre-
treatment lab abnormality);  
- Social admission (eg, patient has no place to sleep);  
- Administrative admission (eg, for yearly physical examination);  
- Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);  
- Optional admission not associated with a precipitating clinical AE (eg, for elective cosmetic 
surgery);  


35 
 
- Hospitalization for observation without a medical AE;  
- Pre-planned treatments or surgical procedures. These should be noted in the baseline  
documentation for the entire protocol and/or for the individual patient;  
- Admission exclusively for the administration of blood products  
  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.  
  
8.7. Severity Assessment  
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria (NCI CTC), (Version 4.03 Publish Date: June 14, 2010).  
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above.  
  
8.8. Causality Assessment  
 
The investigator’s assessment of causality must be provided for all AEs (serious and non- 
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there exists 
a reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be provided. 
If the investigator does not know whether or not the investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Sponsor (see Section on Reporting Requirements). If the investigator's causality 
assessment is “unknown but not related to investigational product”, this should be clearly 
documented on study records.  
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.  
  
8.9. Withdrawal Due to Adverse Events (See Also Section on Patient Withdrawal)  
Withdrawal due to AE should be distinguished from withdrawal due to other causes, according 
to the definition of AE noted earlier, and recorded on the appropriate AE CRF page.  
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.  
  
8.10. 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.  
  


36 
 
8.11. Reporting Requirements  
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.  
  
8.11.1 Serious Adverse Event Reporting Requirements  
Reporting of Serious Adverse Events: Within 24 hours of first awareness of the event 
(immediately if the event is fatal or life-threatening), Principal Investigator will report to Pfizer by 
facsimile any Serious Adverse Event (“SAE,” as defined below) for which reporting is required 
under this provision (as described below). Such SAEs are to be reported for (1) Study subjects 
who are assigned or, in the case of a blinded Study, possibly assigned to receive the Pfizer 
Product or (2) individuals otherwise exposed to the Pfizer Product as described below. Principal 
Investigator should report SAEs as soon as they are determined to meet the definition, even if 
complete information is not yet available.   
Reporting Forms. Principal Investigator will report SAEs using one of the following forms: (1) a 
reporting form approved by the local regulatory authority, (2) a CIOMS form, (3) a Pfizer-
provided Investigator-Initiated Research Serious Adverse Event Form, or (4) any other form 
prospectively approved by Pfizer. The Reportable Event Fax Cover Sheet provided by Pfizer 
must also be included with each SAE submitted.  
 
a. SAE Definition. An SAE is any adverse event, without regard to causality, that is life-
threatening (i.e., causes an immediate risk of death) or that results in any of the following 
outcomes: death; in-patient hospitalization or prolongation of existing hospitalization; 
persistent or significant disability or incapacity (i.e., substantial disruption of the ability to 
conduct normal life functions); or a congenital anomaly or birth defect. Any other medical 
event that, in the medical judgment of the Principal Investigator, may jeopardize the subject 
or may require medical or surgical intervention to prevent one of the outcomes listed above 
is also considered an SAE. A planned medical or surgical procedure is not, in itself, an 
SAE.  
 
b. Exposure during Pregnancy, Exposure during Lactation, Occupational Exposure, and Lack 
Of Effect. Even though there may not be an associated SAE, exposure to the Pfizer 
Product during pregnancy, exposure to the Pfizer Product during lactation, and 
occupational exposure to the Pfizer Product are reportable, and lack of effect of the Pfizer 
Product may also be reportable. These requirements are further explained in the training 
material provided by Pfizer (see Pfizer-Provided Training, below). As used in this 
Agreement, the term SAE will be understood to include exposure during pregnancy, 
exposure during lactation, occupational exposure, and reportable instances of lack of 
effect.  
 
c. Hy’s Law Cases. Cases of potential drug-induced liver injury as assessed by laboratory test 
values (“Hy’s Law Cases”) are 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 as a Hy’s Law Case. As used in this Agreement, the 
term SAE will be understood to also include Hy’s Law Cases.  
 
d. Exclusions from SAE Reporting Requirements. Specifically excluded from the reporting 


37 
 
requirements for SAEs under this provision is any SAE identified in the Protocol as 
anticipated to occur in the Study population at some frequency independent of drug 
exposure, unless the Principal Investigator assesses such an event as related to the Pfizer 
Product.  
 
e. SAE Reporting Period. The SAEs that are subject to this reporting provision are those that 
occur from after the first dose of the Pfizer Product through 28 calendar days after the last 
administration of the Pfizer Product, or longer if so specified in the Protocol. In addition, if 
Principal Investigator becomes aware of an SAE occurring any time after the administration 
of the last dose of the Pfizer Product, Principal Investigator should report that SAE to Pfizer 
if the Principal Investigator suspects a causal relationship between the Pfizer Product and 
the SAE.  
 
f. Follow-Up Information. Principal Investigator will assist Pfizer in investigating any SAE and 
will provide any follow-up information reasonably requested by Pfizer.  
g. 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.  
 
h. Pfizer-Provided Training. Pfizer will make available training material that provides 
information about the SAE reporting requirements for IIR studies. Principal Investigator will 
review this material and share it with any Study staff engaged in the reporting of SAEs.  
 
 8.11.2. Non-Serious Adverse Event Reporting Requirements  
 
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the form for 
collection of SAE information is not the same as the AE CRF. Where the same data are 
collected, the forms must be completed in a consistent manner. For example, the same AE term 
should be used on both forms. AEs should be reported using concise medical terminology on 
the CRFs as well as on the form for collection of SAE information.  
  
8.11.3. Sponsor Reporting Requirements to Regulatory Authorities  
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.  
  
9. CORRELATIVE STUDIES  
 
9.1 Correlative study 1: exploratory analysis of metabolite biomarkers of endocrine 
resistance   
 
Metabolomics analysis of serum: 50 ul of serum sample from each patient will be used for 
metabolomics analysis as described by Xiao et al30 using both ultra-performance liquid 
chromatography mass spectrometer (UPLC MS) and gas chromatography-mass spectrometry 
(GC MS) at Lombardi’s Metabolomics Shared Resources. Analysis will provide a global 
distribution of specific metabolites in patients’ serum at the beginning and end of the study. We 
will use XCMS package (Scripps Center for Metabolomics, La Jolla, CA) to preprocess the MS 
datasets. To avoid multiple freeze-thaws, samples will be collected and stored on site and 


38 
 
transported to the laboratory in one shipment.  
  
9.2 Correlative study 2: identify exosomal signature of endocrine resistance  
 
In this correlative study, we will determine potential biomarkers (RNA and proteins) in serum 
and plasma that are associated with endocrine resistance. Both of these assays will be done at 
SBI Biosciences. As with metabolomics, clinical data such as diabetes, body mass index (BMI) 
or cardiovascular history will be helpful in stratifying our findings.     
RNA-seq: Exosomes will be isolated from plasma and serum, followed by purification of 
exoRNA and building of Illumina NGS libraries. These libraries are then sequenced using a 1x 
50bp single end Illumina HiSeq NGS runs to provide enough depth of RNA sequence 
identification. (SBI's exosome RNA-Seq service can be ordered using catalog# CSEQ400A-1.)  
Mass spectrometry analysis: Exosomes isolated using ultracentrifugation as well as using 
ExoQuick. The MS service will be used to create complete exosome peptide library 
preparations. (SBI's exosome Mass Spec service can be ordered using catalog# CSEQ810A-1.)  
 9.3 Correlative study 3: identify Duffy Null polymorphism (SNP rs2814778 at 
chromosome 1q23.2)   
 
The Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2) is known to protect 
against Plasmodium vivax malaria and has been recently confirmed to be predictive of WBC 
and neutrophil count in African Americans.17 Genotyping of the rs2814778 polymorphism will be 
done using targeted sequencing for those patients who have consented for it.  
   
10. DATA ANALYSIS/STATISTICAL METHODS  
 
10.1. Two stage design, Sample Size, Accrual and Study duration   
 
The study is designed to assess the rate of completion of planned oncology therapy in the 
absence of a hematological event defined as episodes of febrile neutropenia and/or treatment 
discontinuation due to neutropenia. Planned oncology therapy is defined as completion of one 
year of therapy for advanced breast cancer in the absence of disease progression or cessation 
of study drug due to progressive disease or non-neutropenia toxicity.  
 
There is no data about the current proportion of African American patients who meet the 
composite primary endpoint. In the phase II PALOMA-1 study 13% of patients discontinued drug 
due to adverse events.11 Although it is not described what specific adverse event caused the 
treatment discontinuation, we can expect that a significant number of cases was caused by 
neutropenia as the majority of patients (54%) experienced grade 3 or 4 neutropenia. It is 
reported also that there were no cases of febrile neutropenia. It is mentioned in the product 
labeling that febrile neutropenia events have been reported in the IBRANCE® clinical program, 
but the rate of events is not reported. Therefore we estimate that if 80% or more of patients will 
be able to receive palbociclib for advanced breast cancer without developing febrile neutropenia 
or discontinuing drug due to neutropenia it will be clinically meaningful. Therefore we defined a 
completion rate if 80% as considered of clinical relevance, where as a completion rate of 60% is 
considered non clinically meaningful.   
 
Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that the true 


39 
 
completion rate is 60% will be tested against a one-sided alternative. In the first stage, 13 
patients will be accrued. If there are 8 or fewer complete the therapy in the absence of a 
hematological event (defined as episodes of febrile neutropenia and/or treatment 
discontinuation due to neutropenia) in these 13 patients, the study will be stopped. Otherwise, 
22 additional patients will be accrued for a total of 35. The null hypothesis will be rejected if 26 
or more patients complete the therapy in the absence of a hematological event in 35 patients.  
 
This design yields a type I error rate of 0.05 and power of 80% when the true completion rate is 
80%. The intention-to-treat (ITT) population of this trial will be composed of patients who are 
actually enrolled and received at least one dose of palbociclib since they are on study.  
 
We anticipate accruing 35 patients over 12 months across the 3 sites. Historically the three sites 
have experience in accruing African American patients into clinical trials. All patients will be 
followed for a maximum of 12 months. Study duration will have a maximum of 24 months.  
  
10.2. Statistical Analysis Plan  
 
The two-stage analysis will follow the design described in 10.1. An exact confidence interval of 
the completion rate based on binomial calculation will be obtained. We estimate there will be no 
more than 10% episodes of febrile neutropenia.   
 
The outliers and data errors will be checked. Descriptive statistics will be used to characterize 
the demographic profile of the subjects. Frequency and percentages will be used to summarize 
categorical variables. Mean (SD) or median (interquartile range) based on the normalization of 
the data will be used to summarize continuous variables.  
 
The incidence of hematological events during study treatment will be calculated, as well as the 
number of patients who required dose delays in palbociclib attributed to neutropenia, the 
number of patients who required dose reductions in palbociclib therapy attributed to 
neutropenia, the rate of grade 3/4 neutropenia.  
 
For statistical purposes and for evaluation of the primary endpoint, patients who discontinue 
treatment for progressive disease, non-hematologic toxicity or other reasons (that do not include 
febrile neutropenia or other hematological toxicities) will be considered as having completed 
planned oncologic therapy.”  
 
Study drug administration will be described in terms of total and median number of weeks 
administered, doses, and reasons for deviation from planned therapy.  
 
An exploratory subgroup analysis will be performed to see if the primary outcome differs 
between the patients with baseline ANC equal or higher than 1500/uL and the patients with 
baseline ANC between 1000 and 1499/uL. A second exploratory subgroup analysis will be 
performed for those patients who have available ANC before cancer diagnosis: baseline ANC 
prior to cancer diagnosis (equal or higher than 1500/uL versus below 1500/uL) will be correlated 
with primary outcome.  
 
For those with evaluable disease, clinical benefit rate at 24 weeks will be calculated. CBR is 


40 
 
defined as the percentage of patients who achieved complete response, partial response and 
stable disease at 24 weeks.   
 
We will calculate the mean (SD) of specific metabolites at each time point and graphically 
assess these measures over time with clinical response and hematological toxicity. The mean 
change in these variables from baseline to each follow-up point will be calculated. Generalized 
linear model will be utilized for the correlative analysis of clinical response and hematologic 
events.   
  
10.3. Safety stopping rules  
 
Early stopping rules will be incorporated for safety based on febrile neutropenia. If the rate of 
febrile neutropenia is 10% or higher in this population then this would be considered a regimen  
with intermediate risk for febrile neutropenia (10-20%) and consideration of prophylactic myeloid 
growth factors along with additional clinical trials should be given.  
  
If 3 patients experience symptoms of febrile neutropenia related to the treatment, then the trial 
will be terminated. We will accept a rate of less than 10% for events of febrile neutropenia. With 
35 patients enrolled, if 3 febrile neutropenia events are observed, the exact binomial 90% CI 
would be (2.38% to 20.69%). The probability of observing 3 or more febrile neutropenia events, 
for a range of true underlying rates, is summarized in Table 5, indicating for example, that if the 
true rate is as high as 10% then the study has a 0.69 probability of observing three or more 
febrile neutropenia events when 35 patients are treated, and if as high as 15% there is a 0.91 
probability of having observed three or more.  
 
If the rate of febrile neutropenia events is higher than 10%, the likelihood of detecting it is high.  
  
Table 6. Probability of observing at least three febrile neutropenia, for a range of true underlying 
event rates, with n=35 patients.  
   
True probability of febrile neutropenia  
   
0.03  0.04  0.05  0.06  
0.07  
0.1  
0.15  
Probability  0.09  0.16  0.25  0.35  
0.45  
0.69  
0.91  
 
10.4. Safety Analysis  
 
Safety data will be summarized for all patients who received at least one dose of study 
medication.  
   
10.5. Data Safety Monitoring Committee  
 
As this study is an investigator initiated study utilizing FDA approved agents it is 
considered a moderate risk study which requires real-time monitoring by the PI and 
study team and semiannual reviews by the LCCC Data and Safety Monitoring 
Committee (DSMC).  
 


41 
 
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 LCCC 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 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/or Sponsor.  
Based on SAEs, the IRB retains the authority to close the study to further accrual 
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 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 PI and the IRB. If 
the DSMC recommends a study change for patient safety or efficacy reasons the trial PI 
must act to implement the change as expeditiously as possible. In the unlikely event 
that the trial 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 trial 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.  
 
If a recommendation is made to change a trial for reasons other than patient safety or 
efficacy the DSMC will provide an adequate rationale for its decision.  
  
11. QUALITY CONTROL AND QUALITY ASSURANCE  
 
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 


42 
 
that the protocol and Good Clinical Practices (GCPs) are being followed. The 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.  
 
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.  
  
 
 
 
12. DATA HANDLING AND RECORD KEEPING  
  
12.1. Case Report Forms/Electronic Data Record  
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. Blood chemistry laboratory data during the treatment period, 
ECGs, and concomitant medications will not be collected on the CRF; however, Pfizer 
retains the right to view source documents if needed (see Section 10 above). 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.  
 
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 investigator’s site as well as at 
Pfizer and clearly identify those data that will be recorded in the CRF, and for which the 
CRF will stand as the source document.  
  
12.2. Record Retention  
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, eg, CRFs and hospital records), all original signed 


43 
 
informed consent documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation 
of relevant correspondence (eg, letters, meeting minutes, telephone calls reports).  The 
records should be retained by the investigator according to International Conference on 
Harmonisation (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 (eg, 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.  
 
 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.  
  
13. ETHICS  
  
13.1. Institutional Review Board (IRB)  
 
It is the responsibility of the investigator to have prospective approval of the study 
protocol, protocol amendments, informed consent documents, and other relevant 
documents, eg, 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.  
The only circumstance in which an amendment may be initiated prior to IRB approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  
In that event, the investigator must notify the IRB and Pfizer in writing immediately after 
the implementation.  
  
13.2. Ethical Conduct of the Study  
 
This protocol will be conducted in accordance with legal and regulatory requirements, 
as well as the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Patients (Council for International Organizations 
of Medical Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of 
Helsinki (World Medical Association 2008).   
In addition, the study will be conducted in accordance with the protocol, the ICH 
guideline on GCP, and applicable local regulatory requirements and laws.  
  
13.3. Patient Information and Consent  


44 
 
 
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.  
When study data is compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses and other identifiable data will be replaced by a numerical code 
consisting of a numbering system provided by Pfizer in order to de-identify study 
patients.  
 
The study site will maintain a confidential list of subjects who participated in the study 
linking their numerical code to the subject’s actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patient personal 
data consistent with applicable privacy laws. The informed consent/assent document 
must be in compliance with ICH GCP, local regulatory requirements, and legal 
requirements, including applicable privacy 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 representative, the 
patient’s assent (affirmative agreement) must subsequently be obtained when the 
subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a patient’s decisional capacity is so limited she cannot 
reasonably be consulted, as permitted by the IRB and consistent with local regulatory 
and legal requirements, then the patient’s assent may be 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 (eg, decisionally impaired adult), how the investigator determined that 
the person signing the consent was the subject’s legally acceptable representative, the 
consent signer’s relationship to the study subject and that the patient’s assent was 
obtained, or waived.  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  


45 
 
  
13.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP  
 
In the event of any prohibition or restriction imposed (ie, 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:   
• Is generally noted or recognized after it occurs  
• Has no substantive effect on the risks to research participants  
• Has no substantive effect on the scientific integrity of the research plan or the value of the data   
collected   
• Did not result from willful or knowing misconduct on the part of the investigator(s).   
 
 An unplanned protocol variance is considered a violation if the variance:  
• Has harmed or increased the risk of harm to one or more research participants.  
• Has damaged the scientific integrity of the data collected for the study.  
• Results from willful or knowing misconduct on the part of the investigator(s).  
• Demonstrates serious or continuing noncompliance with federal regulations, State laws, or   
University policies.  
 


46 
 
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.    
 
13.5. 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.    
     
14. REFERENCES  
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277-
300.   
2. EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on 
recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005; 365: 1687-
1717.   
3. Wood WC, Muss HB, Solin LJ, Olopade OI. Malignant Tumors of the Breast. In: DeVita VT Jr, 
Hellmann S, Rosenberg SA, editors. Cancer, Principle and Practice of Oncology, 7thEdition, 
Lippincott Williams and Wilkins; 2005; 1415-1477.   
4. Leung, BS, Potter AH. Mode of estrogen action on cell proliferation in CAMA-1 cells. II. 
Sensitivity of G1 phase population. J. Cell. Biochem. 1987; 34:213-225.   
5. Sutherland RL, Hall RE, Taylor IW. Cell proliferation kinetics of MCF-7 human mammary 
carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase 
cells. Cancer Res. 1983; 43:3998-4006.   
6. Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, et al. Phase III 
study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in 
postmenopausal women: analysis of survival and update of efficacy from the international 
Letrozole Breast Cancer Group. Journal of Clinical Oncology 2003; 2101-2109.   
7. Finn RS, Dering J, Conklin D, et al. PD-0332991, a selective cyclin D kinase 4/6 inhibitor, 
preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell 
lines in vitro. Breast Cancer Research 2009; 11(5):R77.   
8. Schwartz GK, LoRusso PM, Dickson MA, et al. Phase I study of PD 0332991, a cyclin-
dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1). Br J Cancer 
2011;104(12):1862-8  
9. Flaherty KT, Lorusso PM, Demichele A, et al. Phase I, dose-escalation trial of the oral cyclin-
dependent kinase 4/6 inhibitor PD 0332991 administered using a 21-day schedule in patients 
with advanced cancer. Clin Cancer Res 2012;18(2):568-76.  


47 
 
10. DeMichele A, Clark AS, Tan KS, et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ 
advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin 
Cancer Res 2015;21(5):995-1001  
11. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-
positive, HER2- negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 
2 study. Lancet Oncol 2015;16(1):25-35   
12. A study of Palbociclib (PD-0332991) + letrozole vs. letrozole for first line treatment of 
postmenopausal women with ER/HER2- advanced breast cancer (PALOMA-2). Available at: 
https://clinicaltrials.gov/ct2/show/NCT01740427. Accessed on August 9, 2015  
13. Turner NC, Ro J, Andre F, Loi S, et al. Palbociclib in Hormone-Receptor-Positive Advanced 
Breast Cancer. N Engl J Med 2015;373(3):209-19  
14. NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical 
Research – Amended, October, 2001  
15. Chen MS Jr, Lara PN, Dang JH, et al. Twenty years post-NIH revitalization Act: enhanicing 
minority participation in clinical trials: laying the groundwork for improving minority clinical trial 
accrual and renewing the case for enhancing minority participation in cancer clinical trials. 
Cancer 2014;120:1091-6   
16. Hsieh MM, Everhart JE, Byrd-Holt DD, et al. Prevalence of neutropenia in the US 
population: age, sex, smoking status, and ethnic differences. Ann Intern Med 2007;146(7):486-
92.  
17. Reich D, Nalls MA, Kao L, et al. Reduced Neutrophil count in people of African descent is 
due to a regulatory variant in the duffy antigen receptor for chemokines gene. PLoS Genet 
2009;5(1).  
18. Hsieh MM, Tisdale JF, Rodgers GP, et al. Neutrophil Count in African Americans: Lowering 
the Target Cutoff to Initiate or resume chemotherapy?. J Clin Oncol 2010; 28,1633-1637.  
19. Hershman D, Weinberg M, Rosner Z, et al. Ethnic neutropenia and treatment delay in 
African American women undergoing chemotherapy for early-stage breast cancer. J Natl 
Cancer Inst 2003;95(20):1545-8.   
20. Shajahan-Haq AN, Cheema MS, Clarke R. Application of metabolomics in drug resistant 
breast cancer research. Metabolites 2015;5(1):100-18.   
21. Nowicki S, Gottlieb E. Oncometabolites: tailoring our genes. FEBS J. 2015;282(15):2796-
805  
22. Gunther UL. Metabolomics Biomarkers for Breast Cancer. Pathobiology 2015;82(3-4):153-
65.  
23. Shajahan-Haq AN, Cook KL, Schwartz-Roberts JL, et al. MYC regulates the unfolded 
protein response and glucose and glutamine uptake in endocrine resistant breast cancer. Mol 
Cancer 2014;13:239.  
24. Asiago VM, Alvarado LZ, Shanaiah N, et al. Early detection of recurrent breast cancer using 
metabolite profiling. Cancer Res 2010;70(21):8309-18.  
25. Lowry MC, Gallagher WM, O’Driscoll L. The role of exomes in Breast Cancer. Clin Chem 
2015 Oct 14. Epub ahead of print.  
26. Yu S, Cao H, Shen B, et al. Tumor-derived exosomes in cancer progression and treatment 
failure. Oncotarget 2015 Oct 7. Epub ahead of print.  
27. Yu DD, Wu Y, Zhang XH, et al. Exosomes from adriamycin-resistant breast cancer cells 
transmit resistance partly by delivering miR-222. Tumour Biol 2015 Oct 2. Epub ahead of print.  
28. Lv MM, Zhu XY, Chen WX, et al. Exosomes mediate drug resistance transfer in MCF-7 
breast cancer cells and a probable mechanism is delivery of P-glycoprotein. Tumour Biol 
2014;35(11):10773-9  
29. Kelly DL, Kreyenbuhl J, Dixon L, et al. Clozapine underutilization and discontinuation in 
African MAericans due to leucopenia. Schizophr Bull 2007; 33(5): 1221-1224.  
30. Xiao JF, Varghese RS, Zhou B, et al. LC-MS based serum metabolomics for identification of 
hepatocellular carcinoma biomarkers in Egyptian cohort. J Proteome Res 2012;11(12):5914-23.  
 


48 
 
 
  
 
LIST OF APPENDICES  
 
Appendix 1. Eastern Cooperative Oncology Group (ECOG) Performance Status  
Grade  ECOG Performance Status  
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out any work activities.   
Up and about more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair  
5  
Dead  
 
  
* 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.  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
 
  


49 
 
 
 
  
 Appendix 2. List of abbreviations  
  
AE  
Adverse events  
ANC  
Absolute neutrophil count  
BEN  
Benign Ethnic Neutropenia  
CBC  
Complete blood count  
CBR  
Clinical benefit rate  
CDK  
Cyclin dependent kinase  
CRF  
Case Report Form  
CVD  
Cardiovascular disease  
DLT  
Dose-limiting toxicities  
DM  
Diabetes Mellitus  
DSMC  Data and Safety Monitoring Committee  
ECOG  Eastern Cooperative Oncology Group  
ER  
Estrogen Receptor  
FDA  
Food and Drug Administration  
HER2  
Human epidermal growth factor receptor 2  
HR  
Hormone Receptor  
HR  
Hazard ratio  
IRB  
Institutional Board Review  
NCI  
National Cancer Institute  
NIH  
National Institute of Health  
ORR  
Overall response rate  
PFS  
Progression Free Survival  
PI  
Principal Investigator  
PR  
Progesterone Receptor  
PR  
Partial Response  
PS  
Performance status  
Rb  
Retinoblastoma  
RP2D  
Recommended phase 2 dose  
SAE  
Serious Adverse Event  
SD  
Stable Disease  
SNP  
Single Nucleotide Polymorphisms  
TTF  
Time to treatment failure  
TTP  
Time to treatment progression  
WBC  
White blood count  
 
 
 
 
 
 
 
 
 
 


50 
 
 
 
PATIENT MEDICATION DIARY (Palbociclib + Letrozole, Anastrozole, or Exemestane)  
Study: Phase II Safety Study of Palbociclib with Letrozole or Fulvestrant in African 
American Women with Hormone Receptor Positive HER2 Negative Advanced Breast 
Cancer  
Subject #: _________________                Site: ______________  
Cycle #:___________________                Current dose of palbociclib: ___________mg  
Take one Palbociclib capsule with food on Days 1-21.  Take one Letrozole, Anastrozole, or Exemestane tablet 
on Days 1-28.  If you miss a day’s dose entirely, you should NOT make it up the next day.  If you inadvertently 
take 1 extra dose during a day, you should NOT take the next day’s dose.  Unused drug and/or empty bottles 
should be RETURNED to the site at the next study visit.  Please record your diary daily.  Always bring your 
completed patient diary to the clinic at EACH study visit. 
 
 
Date taken 
(mm/dd/yyy)  
  
Palbociclib  
☐ Letrozole 
☐ Anastrozole  
☐ Exemestane  
Comments   
(Please use this section to write down 
explanation for any missed doses)  
Day 1  
    /      /  
☐ 
☐ 
  
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Day 16  
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Day 18  
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Day 19  
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Day 20  
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Day 21  
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Day 22  
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Day 23  
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Day 24  
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Day 25  
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Day 26  
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Day 27 
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Day 28  
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51 
 
 
Patient signature: ____________________________________   Date: _____/_____/_____  
PATIENT MEDICATION DIARY (Palbociclib + Fulvestrant)  
Study: Phase II Safety Study of Palbociclib with Letrozole or Fulvestrant in African 
American Women with Hormone Receptor Positive HER2 Negative Advanced Breast 
Cancer  
Subject #: _________________                Site: ______________  
Cycle #:___________________                Current dose of palbociclib: ___________mg 
 
Take one Palbociclib capsule with food on Days 1-21.  If you miss a day’s dose entirely, you 
should NOT make it up the next day. If you inadvertently take 1 extra dose during a day, you 
should NOT take the next day’s dose. Unused drug and/or empty bottles should be 
RETURNED to the site at the next visit. Please record your diary daily. Always bring your 
completed patient diary to the clinic at EACH study visit. 
 
  
Date taken (mm/dd/yyy)  
  
Palbociclib  
  
Fulvestrant  
Comments   
(Please use this 
section to write 
down explanation 
for any missed 
doses)  
Day 1  
    /      /  
☐ 
☐ 
  
Day 2  
    /      / 
☐ 
 
  
Day 3  
    /      / 
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Day 4  
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Day 5  
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Day 6  
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Day 7  
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Day 8  
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Day 9  
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Day 10  
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Day 11  
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Day 12  
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Day 13  
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Day 14  
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Day 15  
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Day 16  
/      / 
☐ 
 
  
Day 17  
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Day 18  
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Day 19  
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Day 20  
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Day 21  
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Day 22  
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Day 23  
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Day 24  
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Day 25  
/      / 
  
  
  
Day 26  
/      / 
  
  
  
Day 27  
/      / 
  
  
  
Day 28  
/      / 
  
  
  


52 
 
 
  
Patient signature: ____________________________________   Date: _____/_____/_____