Clinical trial NCT02668666
Conditions: Hormone Receptor Positive Malignant Neoplasm of Breast Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Estrogen Receptor Positive Breast Cancer Progesterone Receptor Positive Tumor Metastatic Breast Cancer
Keywords: Palbociclib Tamoxifen CDK4/6 Inhibitor
Sponsor: Oana Danciu, MD
Start date: 2017-02-01; Completion date: 2023-10-24
Enrollment: 49 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination with tamoxifen in women with HR(+)/HER2(-) advanced breast cancer who have not received prior systemic anticancer therapies for their advanced/metastatic disease.

Detailed description:
OUTLINE: This is a multi-center trial.

INVESTIGATIONAL TREATMENT:

* Palbociclib 125 mg will be administered orally once daily on days 1-21 (D1-D21) of each 28-day cycle. Subjects will not take palbociclib on D22-D28.
* Tamoxifen 20 mg will be administered orally once daily for every day of the 28-day cycle (i.e., continuously).

Palbociclib should be taken with food in combination with tamoxifen. Subjects should take their dose at approximately the same time each day.

It is encouraged, but not mandatory, that premenopausal subjects will also receive treatment with goserelin or equivalent (e.g., Lupron) given as an injectable subcutaneous implant on D1 of every 28 days cycle or every 3 months.

Disease assessments will be performed at the completion of every 2 cycles.

Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 months after discontinuation of study drug.

To demonstrate adequate organ function, all screening labs should be performed within 14 days prior to registration for protocol therapy:

Hematological (must meet ALL of the following criteria):

* Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L
* Hemoglobin ≥ 9 g/dL
* Platelet count ≥ 100 × 10 9/L

Renal (must meet ONE of the following criteria):

* Serum creatinine ≤ 1.5 × ULN
* Serum creatinine \> 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min

Hepatic (must meet ALL of the following criteria):

* Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
* Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
* Total serum bilirubin ≤ 1.5 × ULN

Arms: arm 1: Subjects will be enrolled to determine progression-free survival (PFS) in subjects with HR(+)/HER2(-) advanced breast cancer who have not received prior systemic anti-cancer therapies.

Palbociclib 125 mg will be administered orally once daily on days D1-D21 of each 28-day cycle. Subjects will not take palbociclib on D22-D28.

Tamoxifen 20 mg will be administered orally once daily for every day of the 28-day cycle (i.e., continuously).
Interventions: intervention 1: Palbociclib intervention 2: Tamoxifen
Intervention descriptions: intervention 1: Palbociclib 125 mg will be administered orally once daily on days D1-D21 of each 28-day cycle. Subjects will not take palbociclib on D22-D28. intervention 2: Tamoxifen 20 mg will be administered orally once daily for every day of the 28-day cycle (i.e., continuously).

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 of 52 
 
A Single Arm Phase II Study of Palbociclib in Combination with Tamoxifen as 
First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer:  
Big Ten Cancer Research Consortium BTCRC-BRE15-016 
 
 
Principal Investigator 
Oana Danciu, MD 
University of Illinois at Chicago 
 
Co-Investigator 
Kari Wisinski, MD 
University of Wisconsin 
 
Statistician 
Menggang Yu, PhD 
University of Wisconsin 
 
Trial Supported by  
Pfizer Inc. 
Pfizer reference number: WI208796 
 
Investigational New Drug (IND) Number: 
Exempted by FDA on 22JAN2016 
 
Trial Management by 
BTCRC Administrative Headquarters at Hoosier Cancer Research Network 
500 N. Meridian Street, Suite 100 
Indianapolis, IN 46204 
 
 
 
 
Initial Protocol Version Date:  
10FEB2016 
 
Amendment Version Date: 
14MAR2017 
08MAY2017 
26JUN2018  
21JUN2019  
23JAN2020(current) 


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PROTOCOL SIGNATURE PAGE  
 
A Single Arm Phase II Study of Palbociclib in Combination with Tamoxifen as First Line 
Therapy for Metastatic Hormone Receptor Positive Breast Cancer: 
Big Ten Cancer Research Consortium BTCRC-BRE15-016 
 
VERSION DATE:  23JAN2020 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to 
the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual. I 
will accept the monitor’s overseeing of the study. I will promptly submit the protocol to applicable 
ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
 
 
       Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND EMAIL TO BTCRC ADMINISTRATIVE HEADQUARTERS  
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to BTCRC Administrative Headquarters and keep a record 
for your files. 


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STUDY SYNOPSIS 
 
TITLE 
A Single Arm Phase II Study of Palbociclib in Combination with Tamoxifen as 
First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer: 
Big Ten Cancer Research Consortium BTCRC-BRE15-016 
PHASE  
Phase II 
OBJECTIVES 
Primary Objectives: 
To estimate the activity of the combination of palbociclib and tamoxifen in first 
line therapy for subjects with HR(+)/HER2(-) advanced breast cancer who have 
not received prior systemic anti-cancer therapies for their advanced/metastatic 
disease, assessed by progression free survival (PFS) 
 
Secondary Objective(s):  
To evaluate: 
 
safety and tolerability 
 
response rates (complete or partial response) (RR) based on RECIST 1.1 or 
MDA Criteria (for patients with bone only disease) 
 
clinical benefit rate (CBR; complete, partial response, or stable disease lasting 
24 weeks or longer) based on RECIST 1.1 or MDA Criteria 
 
2-year overall survival (OS) 
 
Correlative Objectives, if funding is secured:  
 
Perform proteomic analysis of plasma exosomes to identify potential 
mechanisms of primary and secondary resistance to tamoxifen/palbociclib. 
 
Analyze tumor specimens for protein expression of candidate markers of 
primary resistance. 
 
Compare difference in response for subjects presenting with de novo 
metastatic breast cancer to subjects that progressed while on aromatase 
inhibitors 
 
Compare differences in response and toxicity profile in African American and 
Hispanic subjects to Caucasian subjects 
STUDY DESIGN 
Single arm phase II study  
TOTAL NUMBER 
OF SUBJECTS  
Up to 48 subjects 
KEY ELIGIBILITY 
CRITERIA  
1. Age ≥ 18 years 
2. Locally advanced, locoregionally recurrent, or metastatic disease, not 
amenable to curative therapy 
3. Histologically and/or cytologically confirmed diagnosis of ER positive and/or 
PR positive (ER>1%, PR>1%), Her2 negative breast cancer 
4. No prior systemic anti-cancer therapy for advanced HR+ positive disease 
5. Eastern Cooperative Oncology Group PS 0-2 
6. Life expectancy greater than 4 months 
7. Pre or postmenopausal women are eligible  
8. Adequate hematologic function, as defined as meeting all three of the 
following criteria: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, and 
b. Platelets ≥ 100 × 109/L, and 


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c. Hemoglobin (Hgb) ≥ 9.0 g/dL 
9. Adequate renal function, as defined by either of the following criteria: 
a. Serum creatinine ≤ 1.5 × upper limit of normal (ULN), 
b. OR, if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate 
(eGFR) ≥ 40 mL/min 
10. Adequate hepatic function, as defined by all of the following: 
a. aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for 
subjects with known hepatic metastases and 
b. alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for 
subjects with known hepatic metastases and 
c. Total serum bilirubin ≤ 1.5 × ULN 
11. Metastatic disease evaluable on imaging studies. Subject may have 
measurable disease as per RECIST 1.1 or bone-only disease as per MDA 
criteria. Bone-only subjects are also eligible if their disease can be 
documented/ evaluated by bone scans, PET or MRI 
12. Negative pregnancy test for female subjects with reproductive potential, and 
agreement of all female subjects of reproductive potential to use a reliable 
form of contraception during the study and for 120 days after the last dose of 
study drug. 
13. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures. 
14. Signed and dated informed consent document indicating that the subject (or 
legally acceptable representative) has been informed of all pertinent aspects of 
the trial prior to enrollment. 
OUTCOME 
MEASURES 
Progression free survival (PFS)  
STATISTICAL 
CONSIDERATIONS 
The primary endpoint is progression free survival (PFS) as assessed by RECIST 
v1.1 criteria Previous studies identified progression free survival with tamoxifen of 
15 months in first line treatment for breast cancer. With assumptions of 80% power 
to detect median 25 months progression free survival in the combination treatment 
over historic data on single agent tamoxifen activity in metastatic breast cancer, the 
sample size will be 48. This sample size assumes 20% censoring rate due to loss to 
follow up, unevaluable, or drop out.    
ENROLLMENT 
PERIOD 
Estimated 24 months 
TOTAL STUDY 
DURATION  
Estimated 48 months 
 
 


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INDEX  
 
SECTION                                                                                                                 
PAGE 
 
SCHEMA .......................................................................................................................................... 6 
1. 
BACKGROUND & RATIONALE .................................................................................. 9 
1.1. 
Introduction ......................................................................................................................... 9 
1.2. 
Study Rationale ................................................................................................................. 10 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................ 11 
2.1. 
Study Objectives ............................................................................................................... 11 
3. 
ELIGIBILITY CRITERIA ............................................................................................ 12 
3.1. 
Inclusion Criteria ............................................................................................................... 12 
3.2. 
Exclusion Criteria .............................................................................................................. 13 
4. 
SUBJECT REGISTRATION  ........................................................................................ 15 
5. 
TREATMENT PLAN ..................................................................................................... 15 
5.1. 
Overall Design and Study Plan ......................................................................................... 15 
5.2. 
Pre-medication .................................................................................................................. 15 
5.3. 
Drug Administration ......................................................................................................... 16 
5.4. 
Supportive Care ................................................................................................................. 16 
5.5. 
Concomitant Medications ................................................................................................. 17 
5.6. 
Diet/Activity/Other Considerations ................................................................................... 18 
6. 
DOSE DELAYS ............................................................................................................... 19 
6.1. 
Dose Modifications ........................................................................................................... 19 
6.1.1. 
Palbociclib Dose Modifications..................................................................................... 19 
6.1.2. 
Tamoxifen Dose Modifications ..................................................................................... 20 
6.1.3. 
Goserelin Dose Modifications ....................................................................................... 21 
7. 
STUDY CALENDAR & EVALUATIONS [Cycle = 28 days] ..................................... 22 
7.1. 
Screening ........................................................................................................................... 24 
7.2. 
On Treatment..................................................................................................................... 24 
7.3. 
Every three cycles ............................................................................................................. 26 
7.4. 
Off Treatment .................................................................................................................... 26 
7.5. 
Safety Follow-up Evaluations ........................................................................................... 26 
7.6. 
Long Term Follow-up Evaluations (±14 days) ................................................................. 27 
8. 
CRITERIA FOR DISEASE EVALUATION ............................................................... 27 
9. 
BIOLOGICAL CORRELATIVES ................................................................................ 33 
10. 
DRUG INFORMATION ................................................................................................ 36 
11. 
ADVERSE EVENTS ....................................................................................................... 42 
12. 
STATISTICAL CONSIDERATIONS .......................................................................... 45 
13. 
TRIAL MANAGEMENT ............................................................................................... 47 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................... 49 
15. 
ETHICS ............................................................................................................................ 50 
16. 
REFERENCES ................................................................................................................ 51 
 


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BTCRC-BRE15-016 
 
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 SCHEMA 
 
A Single Arm Phase II Study of Palbociclib in Combination with Tamoxifen as First Line 
Therapy for Metastatic Hormone Receptor Positive Breast Cancer 
Big Ten Cancer Research Consortium BTCRC-BRE15-016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will be treated with palbociclib (po) at a 125 mg dose on days 1-21 of the 28-day cycle 
and with 20 mg tamoxifen (po) once a day continuously. Premenopausal subjects may also receive 
treatment with Goserelin (3.6 mg sc every 28 days or 10.8 mg sc every 3 months) or equivalent 
(e.g. Lupron) on day 1 of every treatment cycle. 
Subjects with HR(+)/HER2(-) advanced breast cancer who have not 
received prior systemic anti-cancer therapies  
Palbociclib (125 mg) 
+  
Tamoxifen (20 mg) 
CR, PR or SD 
Follow for progression 
and survival for 2 years 
(±2 months) from 
enrollment. 
Disease Assessment every 2 cycles 
Progression or 
significant toxicity 
Continue 
treatment. 
Discontinue 
treatment. 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
adverse event 
AHQ 
Administrative Headquarters 
AI 
aromatase inhibitor 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATE 
arterial thromboembolic event 
AUC 
area under the curve 
BMP 
basic metabolic panel 
BTCRC 
Big Ten Cancer Research Consortium 
CBC 
complete blood cell count 
CDK 
cyclin-dependent kinase 
CI 
confidence interval 
CLM 
Correlative Laboratory Manual 
cm 
centimeter 
CR 
complete response 
CT 
computed tomography 
CTC 
cytotoxic T cell 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CYP 
cytochrome P450 enzyme 
DCR 
disease control rate 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DMBA 
dimethylbenzanthracene 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
Estimated Glomerular Filtration Rate 
ER+ 
estrogen receptor positive 
FDA 
Food and Drug Administration 
GI 
gastrointestinal 
GnRH 
gonadotropin-releasing hormone 
HER2- 
human epidermal growth factor receptor 2 negative 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
hr 
hour 
HR 
hazard ratio 
HR+ 
hormone receptor positive 


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Abbreviation 
Definition 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IND 
Investigational New Drug 
I/O 
input/output 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
kg 
kilogram 
lb 
pound 
LMWH 
low-molecular-weight heparin 
mg 
milligram 
min 
minute 
mL 
milliliter 
mm3 
cubic millimeters 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NDC 
National Drug Code 
OS 
overall survival 
PD 
progressive disease 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha 
PFS 
progression-free survival 
PR 
partial response 
PR 
progesterone receptor 
PS 
performance status 
Rb 
retinoblastomaprotein 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
response rate 
SAE 
serious adverse event 
SD 
stable disease 
SULT 
sulfotransferase 
T3 
triiodothyronine 
T4 
thyroxine 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
UPIRSO 
unanticipated problems involving risk to subjects or others 
US 
United States 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WOCP 
women of childbearing potential 
wt 
weight 


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1. BACKGROUND & RATIONALE 
 
1.1. 
Introduction 
 
The efficacy of endocrine therapy needs to be improved in patients with hormone receptor positive 
metastatic breast cancer. 
Breast cancer is the most common cancer in women worldwide and more than 1.5 million new breast 
cancer cases are reported each year. Invasive breast cancer is classified based on the presence of estrogen 
receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) antigen. 
Hormone receptor positive (HR+) breast cancer is the most commonly diagnosed subset of breast cancer 
(60-65%), and affects thousands of patients every year. Hormone receptor positive subgroup is defined as 
estrogen receptor positive, progesterone receptor positive or both, and HER 2 negative. Endocrine therapy 
is highly effective for this subset of breast cancer, in both the adjuvant and metastatic settings. Despite 
advances in endocrine therapy, many patients have relapse during or after completing adjuvant therapy. 
Management of these patients remains challenging. Single agent treatment with aromatase inhibitors or 
tamoxifen has shown limited clinical benefit (1, 2). Tamoxifen works by blocking the binding of the 
estrogen receptor in the breast cancer cells and has an overall response rate of 25-30% when used as first-
line therapy for advanced breast cancer (3). Even if HR+ metastatic breast cancer patients respond to 
tamoxifen initially, they eventually develop acquired resistance and their disease progresses, and transition 
to continuous lifelong treatment with chemotherapy. Therefore, improving the efficacy of endocrine 
therapy would benefit a large number of breast cancer patients, and is an unmet medical need. A variety of 
novel agents targeting critical pathways in cellular growth are in development to improve the efficacy of 
endocrine therapy against HR + breast cancer. 
 
Palbociclib, its mechanism of action, and its efficacy in HR+ metastatic breast cancer 
Palbociclib is a reversible, oral, small molecule inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6) 
(4). CDK4 and CDK6 together with cyclin D have important roles in regulation of the G1/S transition via 
regulation of the phosphorylation state of retinoblastomaprotein (Rb). When phosphorylation of pRb 
occurs, it causes release of transcription factors that then allow the transition from G1 to S phase and 
progression of the cell cycle (5). The luminal A and B subtypes of breast cancer (85 % of which are 
HR+/Her2 negative) have high rates of cyclin D/CDK activation; in the luminal A and B subtypes, cyclin 
D1 (CCND1) amplifications were observed in 29% and 58% , and CDK4 amplifications were observed in 
14% and 25% respectively (6). Luminal A subtype tumors also have loss of CDKN2A which encodes 
p16Ink4a, a CDK inhibitor (7). The luminal subtypes also maintain expression of Rb, which is essential for 
benefit from treatment with a CDK4/6 inhibitor. (8) Patients with HR + breast cancer exhibiting a gene 
expression signature of Rb loss had shorter recurrence-free survival following adjuvant tamoxifen (9). A 
tumor gene expression signature of E2F activation was associated with higher residual tumor cell 
proliferation following pre-surgical AI therapy. Therefore, activation of the CDK4/CDK6/E2F axis 
promotes endocrine resistance, and treatment with a CDK4/6 inhibitor or knockdown of CDK4 expression 
abrogates endocrine-resistant cell proliferation. Targeting the inhibition of CDK 4/6 pathway is an 
attractive therapeutic strategy.  
 
The therapeutic effect of palbociclib in breast cancer was tested preclinically in a large panel of human 
breast cancer cell lines (10). In the clinical setting, palbociclib has been studied as monotherapy in phase I 
studies, as well as in combination with endocrine therapy. A prior phase II study suggested that single 
agent palbociclib induced responses in HR + breast cancer (11). In this trial, 7% of patients had a partial 
response (PR) and 50% had stable disease (SD). The overall clinical benefit was 21% among 33 ER + 
patients. Median progression free survival was 3.8 months for patients with ER+HER2- disease. A 


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randomized phase II trial of letrozole with or without palbociclib as first line treatment (PALOMA-
1/TRIO-18) was conducted in postmenopausal women with HR+/ human epidermal growth factor receptor 
2 negative (HER2-) metastatic breast cancer (12). At the time of the final analysis for progression-free 
survival (PFS) (median follow-up 29·6 months [95% CI 27·9–36·0] for the palbociclib plus letrozole group 
and 27·9 months [25·5–31·1] for the letrozole group), 41 PFS events had occurred in the palbociclib plus 
letrozole group and 59 in the letrozole group. Median PFS was 10·2 months (95% CI 5·7–12·6) for the 
letrozole group and 20·2 months (13·8–27·5) for the palbociclib plus letrozole group (HR 0·488, 95% CI 
0·319–0·748; one-sided p=0·0004). The results of this trial led to FDA approval of palbociclib in 
combination with letrozole as first line therapy for patients with metastatic breast cancer. The 
recommended starting dose is 125 mg orally daily for 21 days followed by 7 days off in 28 days cycles in 
combination with letrozole 2.5 mg orally daily continuously. Most common adverse events from the phase 
II PALOMA-1 trial were neutropenia (48% grade 3), leukopenia (19% grade 3) and fatigue (36% grade 2) 
(12). Notably, despite the increased incidence of neutropenia, no neutropenic fever was reported. Dose 
delay was required in 45 % of patients in the combination arm and dose reduction was required in 40% of 
patients. Findings from the confirmatory trial PALOMA-2, a randomized phase III trial of palbociclib plus 
letrozole versus placebo plus letrozole for the first-line treatment of post-manopausal patients with 
ER+/HER2- advanced breast cancer is expected to be reported later this year. In second line setting, 
palbociclib plus fulvestrant demonstrated an improvement in PFS compared with placebo plus fulvestrant 
in the PALOMA-3 phase III trial (13). The median PFS was 9.2 months for the palbociclib-containing 
regimen and 3.8 months for the fulvestrant plus placebo arm.  
 
Palbociclib may have synergistic anti-cancer effects with tamoxifen based on a phase I trial without 
either drug affecting each other’s pharmacokinetic profile. 
Preclinical data showed that in combination with tamoxifen, palbociclib had synergistic growth inhibitory 
activity as well as efficacy in a model of acquired tamoxifen resistance (11). Studies evaluating the role of 
cyclin D1 in breast cancer support the observations of the activity of CDK4/6 inhibitor in luminal ER-
positive breast cancer, its synergism with tamoxifen in cell lines that are sensitive to hormone 
manipulation, as well as the reversal of resistance of those that have acquired a resistant phenotype to anti-
estrogen therapy. Estrogen effects on cell cycle progression are tightly linked to expression of cyclin D1 
(14). Cyclin D1 amplification and/or overexpression has been more commonly associated with an ER-
positive breast cancer subtype (15) and, is associated with tamoxifen resistance (16, 17). 
 
Tamoxifen could affect the metabolism of co-administered drugs that are substrates for CYP3A4 since in 
vitro data indicate tamoxifen is a reversible and time-dependent inhibitor of CYP3A4 (18) as well as an 
inducer of CYP3A4 (19). Palbociclib is mainly metabolized by CYP3A4. A clinical drug interaction study 
of tamoxifen and palbociclib revealed that there were no significant changes in exposure in the presence of 
steady-state levels of tamoxifen when compared with exposure when given alone (20). Therefore based on 
this phase I study, tamoxifen is not expected to affect palbociclib pharmacokinetics due to CYP-mediated 
interactions. 
 
1.2. 
Study Rationale 
Combining palbociclib with tamoxifen in first line treatment of metastatic HR+ breast cancer offers an 
appealing alternative to other endocrine combinations. Tamoxifen remains an active endocrine therapy for 
pre- and post-menopausal women with hormone receptor (HR) positive breast cancers.  In addition, most 
postmenopausal women with HR+ breast cancer receive aromatase inhibitors (AI) as adjuvant endocrine 
therapy. The group of women that progress on adjuvant therapy with AIs may not benefit from the addition 
of CDK 4/6 inhibition to their current endocrine therapy.  Although fulvestrant could be considered in this 
setting, the cost and inconvenience of monthly injections remains a challenge.  Thus, the combination of 


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tamoxifen with palbociclib will offer the option of continuing oral combination endocrine therapy with 
CDK 4/6 inhibition. The combination with tamoxifen could offer a different spectrum of side effects, and it 
may be better tolerated by subjects with osteoporosis or advanced arthritis. Accordingly, we will conduct a 
Phase II study to estimate the response rates of the combination of palbociclib and tamoxifen in first line 
therapy for subjects with HR(+)/HER2(-) advanced breast cancer who have not received prior systemic 
anti-cancer therapies for their advanced/metastatic disease.   
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1. 
Study Objectives 
 
2.1.1. Primary Objective 
The primary objective of the Phase II study is to estimate the activity of the combination of palbociclib 
and tamoxifen in first line therapy for subjects with HR(+)/HER2(-) advanced breast cancer who have 
not received prior systemic anti-cancer therapies for their advanced/metastatic disease, assessed by 
progression free survival (PFS) per local assessment based on RECIST 1.1  
2.1.2. Secondary Objectives 
 Characterize safety and tolerability of palbociclib and tamoxifen in first line therapy for subjects 
with HR(+)/HER2(-) advanced breast cancer who have not received prior systemic anti-cancer 
therapies for their advanced/metastatic disease. 
 Evaluate response rates (complete or partial response) (RR) per local assessment and RECIST 1.1 or 
MDA criteria in subjects with HR(+)/HER2(-) advanced breast cancer who have not received prior 
systemic anti-cancer therapies for their advanced/metastatic disease treated with palbociclib in 
combination with tamoxifen. 
 Evaluate clinical benefit rate RR (complete, partial response, or stable disease, lasting 24 weeks or 
longer) based on RECIST 1.1 or MDA criteria in subjects with HR(+)/HER2(-) advanced breast 
cancer who have not received prior systemic anti-cancer therapies for their advanced/metastatic 
disease treated with palbociclib in combination with tamoxifen. 
 Measure overall survival (OS) at 2 years in subjects with HR(+)/HER2(-) advanced breast cancer 
who have not received prior systemic anti-cancer therapies for their advanced/metastatic disease 
treated with palbociclib in combination with tamoxifen. 
2.1.3. Correlative Objectives, if funding is secured 
 Perform proteomic analysis of plasma exosomes to identify potential mechanisms of primary and 
secondary resistance to tamoxifen/palbociclib. 
 Analyze tumor specimens for protein expression of candidate markers of primary resistance. 
 Compare difference in response for subjects presenting with de novo metastatic breast cancer to 
subjects that progressed while on aromatase inhibitors. 
 Compare differences in response and toxicity profile in African American and Hispanic subjects to 
Caucasian subjects.  
 Compare differences in response and toxicity profile between pre- and post-menopausal women.


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3. ELIGIBILITY CRITERIA 
 
Study entry is open to subjects of any ethnic background. While there will be every effort to seek out and 
include minorities, the subject population is expected to be no different than that of other advanced solid 
tumor cancer studies at each participating institution. 
 
3.1. 
Inclusion Criteria 
Subjects must meet all of the following applicable inclusion criteria to participate in this study: 
 
3.1.1 Male or female ≥ 18 years of age at time of consent.  
NOTE: Both pre- and post-menopausal women are eligible. 
Pre-menopausal status is defined as either: 
-Last menstrual period within the last 12 months 
-In case of therapy-induced amenorrhea, plasma estradiol and /or FSH is in the premenopausal range per 
local normal range. 
 
3.1.2 Locally advanced, locoregionally recurrent, or metastatic disease, not amenable to curative therapy. 
NOTE: Although not required as a protocol procedure, a patient with a new metastatic lesion should be 
considered for biopsy whenever possible to reassess ER/PR/HER2 status if clinically indicated. If a 
biopsy is prospectively done as part of standard of care, the study would like to store samples for 
correlative research. 
 
3.1.3 Histologically and/or cytologically confirmed diagnosis of ER positive and/or PR positive (ER >1%, PR 
>1%), HER2 negative breast cancer. 
NOTE: Subject has HER2-negative breast cancer (based on most recently analyzed biopsy) is defined as 
a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ 
hybridization (e.g. FISH, CISH, SISH, DISH, etc.) test is required by local laboratory testing. 
 
3.1.4 Metastatic disease evaluable on imaging studies. Subjects may have measurable disease as per RECIST 
1.1 or bone-only disease.  
NOTE: Bone-only subjects are eligible if their disease can be documented/ evaluated by bone scans, CT 
or MRI. Their disease will be assessed using MDA criteria.  
NOTE: Previously irradiated lesions are eligible as a target lesion only if there is documented 
progression of the lesion after irradiation. 
 
3.1.5 No prior systemic anti-cancer therapy for advanced HR+ disease.   
NOTE: Subjects receiving adjuvant treatment with aromatase inhibitors at time of recurrence are 
allowed to participate. There is no AI washout period required.  
 
3.1.6 Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 
 
3.1.7 Adequate hepatic function within 14 days prior to registration for protocol therapy defined as meeting 
all of the following criteria: 
 aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic 
metastases and 
 alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic 
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 total serum bilirubin ≤ 1.5 × ULN  
 
3.1.8 Adequate renal function within 14 days prior to registration for protocol therapy defined by either of the 
following criteria:  
 serum creatinine ≤ 1.5 × ULN 
 OR if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min 
 
3.1.9 Adequate hematologic function within 14 days prior to registration for protocol therapy defined as 
meeting all of the following criteria: 
 hemoglobin ≥ 9 g/dL 
 and absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
 and platelet count ≥ 100 × 109/L 
 
3.1.10 Provided written informed consent and HIPAA authorization for release of personal health information, 
approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC). 
NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 
 
3.1.11 Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A negative serum or 
urine pregnancy test is required within 72 hours of study registration from women of childbearing 
potential. If the urine test cannot be confirmed as negative, a serum pregnancy test will be required. 
 
3.1.12 Women of childbearing potential (WOCP) must be willing to use two effective methods of birth control 
such as use of a double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal 
jellies or cream), or total abstinence for the course of the study until 120 days after the last dose of study 
drug. The use of hormonal contraceptives is discouraged. 
NOTE: Women are considered to be of childbearing potential unless they are postmenopausal for at 
least 12 consecutive months or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy). 
 
3.1.13 Male subjects capable of fathering a child must agree to use adequate contraception (see section 5.6) or 
total abstinence for the course of the study until 120 days after the last dose of the study drug. 
NOTE: Male subjects will be considered as capable of fathering a child unless they have azoospermia 
(whether due to having had a vasectomy or due to an underlying medical condition). 
 
3.1.14 Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other 
study procedures. 
 
3.1.15 Co-enrollment in an imaging biomarker study or other non-therapeutic study is allowed. 
 
3.2. 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
3.2.1 Prior treatment with any CDK 4/6 inhibitor. 
 
3.2.2 Confirmed diagnosis of HER2 positive disease. 
 


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3.2.3 Known uncontrolled or symptomatic CNS metastases. Subjects with known brain metastasis will only 
be eligible after their tumors have been treated with definitive resection and /or radiotherapy and they 
are neurologically stable for at least 1 month off steroids 
 
3.2.4 Advanced, symptomatic, visceral spread with a life expectancy less than 4 months. 
 
3.2.5 Prior (neo)adjuvant treatment with tamoxifen within the 12 months before study entry. 
 
3.2.6 Prior history of blood clots, pulmonary embolism or deep vein thrombosis. 
 
3.2.7 Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of 
the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, or small bowel resection). 
 
3.2.8 Concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately 
treated basal cell carcinoma, squamous cell skin carcinoma, non-melanomatous skin cancer or curatively 
resected cervical cancer. 
 
3.2.9 Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s 
judgment, contraindicate subject participation in the clinical study 
 
3.2.10 Currently receiving any of the following substances and cannot be discontinued 7 days prior to study 
registration: 
 Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, 
pomelos, star-fruit, and Seville oranges. 
 Medications that have a narrow therapeutic window and are predominantly metabolized through 
CYP3A4/5. 
 Known strong inducers or inhibitors of CYP2D6. 
 
3.2.11 Major surgery within 14 days prior to study registration or has not recovered from major side effects of 
surgery. 
 
3.2.12 Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies]. 
 
3.2.13 Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected) (testing not mandatory) 
 
3.2.14 Any clinically significant infection defined as any acute viral, bacterial, or fungal infection that requires 
specific treatment.  
NOTE: Anti-infective treatment must be completed ≥ 7 days prior to study registration. 
 
3.2.15 Known allergy to palbociclib or any of its excipients 
 
3.2.16 Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study registration. NOTE: 
if fracture is at a metastatic site, is chronic, and no surgical treatment is planned, the subject can be 
enrolled. 
 


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3.2.17 Any condition that, in the opinion of the investigator, might jeopardize the safety of the subject or 
interfere with protocol compliance. 
 
3.2.18 Any mental or medical condition that prevents the subject from giving informed consent or participating 
in the trial. 
 
3.2.19 Treatment with any therapeutic investigational agent within 28 days prior to registration for protocol 
therapy. The subject must have recovered from the acute toxic effects of the regimen. 
 
4. SUBJECT REGISTRATION  
All subjects must be registered through the Big Ten Cancer Research Consortium (BTCRC) Administrative 
Headquarters’ (AHQ) electronic data capture (EDC) system OnCore®. A subject is considered registered 
when an ‘On Study’ date is entered into OnCore®. 
 
Subjects must be registered after signing consent but prior to starting protocol therapy. Protocol therapy must 
begin therapy within 5 business days of registration.   
 
Subjects Who Do Not Begin Study Treatment 
If subject signs consent, is registered to the study, and later is not able to begin the planned study treatment, 
for whatever reason, the subject will be removed from study and treated at the physician’s discretion. The 
subject will be considered a screen/baseline failure and be replaced. The reason for removal from study will 
be clearly indicated in EDC system.   
 
If a subject begins treatment, and then is discontinued for whatever reason, the subject must be followed per 
section 7.5. 
 
5. TREATMENT PLAN 
 
5.1. 
Overall Design and Study Plan 
This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination 
with tamoxifen in subjects with HR(+)/HER2(-) advanced breast cancer who have not received prior systemic 
anti-cancer therapies for their advanced/metastatic disease. The primary objective of the Phase II trial is to 
determine progression free survival (PFS) based on RECIST 1.1 Treatment will continue until disease 
progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the 
therapy itself, or from other causes. Subjects, who voluntarily stop the study, have progressive disease, or 
unacceptable toxicities will be followed for a total of 24 months after discontinuation of study drug.  
 
If funding is secured, correlative research analyses includes correlating alterations in circulating tumor DNA 
at the time of progression, correlating molecular alterations of genes associated with ER+ breast cancer in 
tumor tissue samples with clinical outcome and at the time of progression, comparing difference in response 
for subjects presenting with de novo metastatic breast cancer to subjects that progressed while on aromatase 
inhibitors, and comparing differences in response and toxicity profile in African American and Hispanic 
subjects to Caucasian subjects. 
 
5.2. 
Pre-medication  
Pre-medication is not required but may be administered per physician discretion. 
 
 


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5.3. 
Drug Administration 
 
5.3.1. Palbociclib + Tamoxifen Administration 
The palbociclib dose will be 125 mg administered orally once daily on days 1-21 of each 28-day cycle. 
Subjects will not take palbociclib on days 22-28. The tamoxifen dose will be 20 mg administered orally once 
daily for every day of the 28-day cycle (i.e., continuously). It is encouraged but not mandatory that 
premenopausal subjects will also receive treatment with Goserelin or equivalent (e.g. Lupron) given as an 
injectable subcutaneous implant on day 1 of every 28 days cycle or every 3 months. 
 
Drug 
Dose 
Route 
Schedule 
Cycle Length 
Palbociclib 
125mg 
Oral 
Days 1-21 
28 days 
Tamoxifen 
20mg 
Oral 
Continuous 
 
Palbociclib should be taken with food in combination with Tamoxifen. Subjects should be encouraged to take 
their dose at approximately the same time each day.  
 
5.3.2. Missed Doses: 
Missed doses may be taken up to 6 hours of the time that the dose was scheduled. If the timing is beyond 6 
hours, the subject will skip the dose and take the next dose as scheduled.  
 
If emesis occurs after study medication ingestion and whole capsule(s) are visible in the vomitus, replacement 
capsule(s) should be taken; otherwise, the dose will not be re-administered and subjects should simply adhere 
to the dosing schedule and resume dosing at the next scheduled time with the prescribed dosage. Subjects 
should record the time of the emesis in their dosing diary (see Documents/Info tab of the EDC). Under no 
circumstance should a subject repeat a dose or double-up doses.  
 
5.4. 
Supportive Care 
Optimal patient care is to be given to all subjects. 
 
Subjects should receive full supportive care during the study, including transfusion of blood and blood 
products, treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates (or denosumab), when 
appropriate.  
 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating investigator 
including but not limited to the items outlined below: 
 
 Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration should be given 
in subsequent cycles to the administration of prophylactic antiemetic therapy according to standard 
institutional practice. If prophylactic antiemetic therapy is needed, 5-HT3 receptor antagonists (without 
corticosteroids) should be tried first. Due to the potential of benzodiazepines to cause sedation, the use of 
benzodiazepines for antiemetic prophylaxis should be reserved for subjects who cannot be satisfactorily 
managed otherwise. Subjects should be strongly encouraged to maintain liberal oral fluid intake. 
 Anti-infectives: Subjects with a documented infectious complication should receive oral or IV antibiotics 
or other anti-infective agents as considered appropriate by the treating investigator for a given infectious 
condition, according to standard institutional practice. 


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 Prophylactic myeloid growth factors are not permitted for prevention of neutropenia and are only 
permitted if clinically indicated in response to a clinically significant episode of neutropenia. 
 
5.5. 
Concomitant Medications 
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing trial. If there 
is a clinical indication for one of these or other medications specifically prohibited during the trial, 
discontinuation from trial therapy may be required. The site investigator should discuss any questions 
regarding this with the sponsor-investigator by contacting the BTCRC Project Manager. The final decision 
on any supportive therapy rests with the investigator and/or the subject's primary physician. However, the 
decision to continue the subject on trial therapy requires the mutual agreement of the local Investigator, the 
sponsor-investigator, and the subject.  
 
Permitted Concomitant Medications and Procedures 
All treatments the investigator considers necessary for a subject’s welfare may be administered at the 
discretion of the investigator in keeping with the community standards of medical care. All concomitant 
medications will be recorded on the electronic case report form (eCRF). 
 
Palliative radiation is permitted but palbociclib must be withheld throughout the course of radiotherapy. 
Palliative RT should not be delivered to a target lesion and it should not encompass more than 25% of the 
irradiated bone marrow. The reason for radiotherapy must be clearly documented and progression as per 
RECIST 1.1 must be ruled out. No dose modification of study treatment is mandated after completion 
palliative radiotherapy. 
 
If elective surgery is needed during study, it is recommended the surgery be scheduled between treatment 
cycles. Palbociclib should be withheld 14 days prior to surgery. The next cycle of treatment may be delayed 
up to 4 weeks to allow for additional recovery at the discretion of the investigator.   
 
All concomitant medications received within 28 days before the first dose of trial treatment and 30 days after 
the last dose of study drug should be recorded. Concomitant medications administered beyond 30 days after 
the last dose of trial treatment should be recorded for SAEs as defined in Section 11. 
 
Antiemetic agents may be administered at the discretion of the investigator but are not commonly required as 
a prophylactic agent. All other manifestations of the subject’s malignancy should be treated at the discretion 
of the investigator. 
 
All other medical conditions should be treated at the discretion of the investigator in accordance with local 
community standards of medical care. 
 
The Effects of Other Drugs on Palbociclib 
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1.  
 
The use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
verapamil, and voriconazole) should be avoided as these drugs could increase plasma levels of palbociclib.  
 
The use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John's Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) should be avoided 
as these drugs could decrease plasma levels of palbociclib.  


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The use of strong inhibitors or inducers of CYP2D6 (Bupropion, dacomitinib, fluoxetine, paroxetine, 
quinidine) should be avoided  
 
The Effects of Palbociclib on Other Drugs 
In vivo, palbociclib is a time-dependent inhibitor of CYP3A. 
 
Coadministration of midazolam with multiple doses of palbociclib increased the midazolam plasma exposure 
by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive 
CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as 
palbociclib may increase their exposure. 
 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase of 
this trial: 
 Anti-cancer systemic chemotherapy or biological therapy not specified in this protocol 
 Other investigational and antineoplastic therapies 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned treatments 
for clinical management should be removed from the trial.   
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.6. 
Diet/Activity/Other Considerations 
 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, 
nausea, or vomiting. 
 
Contraception 
Palbociclib may have adverse effects on a fetus in utero. Non-pregnant, non-breast-feeding women may be 
enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive. 
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.   
 
It is encouraged but not mandatory that premenopausal subjects will also receive treatment with goserelin or 
equivalent (e.g. Lupron) given as an injectable subcutaneous implant on day 1 of every 28 days cycle or every 
3 months. 
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the partner), 
copper intrauterine device, sponge, or spermicide. The use of hormonal contraceptives is discouraged. 
 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn 
baby) if pregnancy were to occur during the study. In order to participate in the study they must adhere to the 
contraception requirements described above for the duration of the study and at least 120 days following the 
last dose of study drug. If there is any question that a subject will not reliably comply with the requirements 
for contraception, that subject should not be entered into the study. 


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Use in Pregnancy 
If a subject becomes pregnant while on treatment with palbociclib, the subject will immediately be removed 
from the study therapy. All pregnancies must be reported to BTCRC AHQ within 1 business day using the 
Pregnancy Report form (See Documents/Info tab of the EDC).  
 
The study investigator will make every effort to obtain permission to follow the outcome of the pregnancy 
and report the condition of the fetus or newborn to BTCRC AHQ. The site should make every effort to contact 
the subject at least monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to BTCRC AHQ as soon as the information is 
available. If the outcome is a serious adverse event (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn), it will be reported to BTCRC AHQ 
within 1 business day.  
 
Use in Nursing Women 
It is unknown whether palbociclib is excreted in human milk. Since many drugs are excreted in human milk, 
and because of the potential for serious adverse reactions in the nursing infant, subjects who are breast-feeding 
are not eligible for enrollment. 
 
6. DOSE DELAYS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 will be used to grade 
adverse events. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests before and at 
regular intervals during their participation in this study as specified in Section 7. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse events 
requiring protocol therapy interruption or discontinuation at each study visit for the duration of their 
participation in the study.   
 
Subjects discontinued from the study drug for any reason will be evaluated within 30 days (± 7) of the last 
dose of study drug. 
 
6.1. 
Dose Modifications 
 
6.1.1. Palbociclib Dose Modifications 
 
Table 1. Dose Modifications 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, the subject will be 
discontinued from study treatment.
 
 
 


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Palbociclib will be withheld for drug-related >Grade 3 hematologic toxicities, non-hematological toxicity 
≥Grade 3 including laboratory abnormalities and severe or life-threatening AEs as per Table 2 below. 
 
Table 2: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
Hematological 
Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Except lymphopenia 
(unless associated 
with clinical events, 
e.g.., opportunistic 
infections) 
Withhold 
initiation of 
next cycle. 
 
Repeated 
hematologic 
monitoring 
one week later
Toxicity resolves 
to Grade <2 
 
No dose 
adjustment is 
required 
Toxicity does not 
resolve within 4 
weeks of last study 
drug administration 
Permanent 
discontinuation 
should be 
considered for any 
severe or life-
threatening event 
Grade 3 ANC (<1000 
to 500/mm3) + 
Fever>38.5o C and/or 
infection 
 
Grade 3 Plt count 
(<50000 to 25000/ 
mm3) with clinically 
significant bleeding  
Yes 
 
Toxicity resolves 
to Grade <2 
(ANC>1000/ mm3, 
platelets > 
50000/mm3) 
Resume at next 
lower dose 
4* 
*Except lymphopenia 
(unless associated 
with clinical events, 
e.g.., opportunistic 
infections) 
Yes 
Toxicity resolves 
to Grade <2 
Resume at next 
lower dose  
Non-
hematological 
toxicity† 
 
Note:  
Exception to be 
treated similar 
to grade 1 
toxicity  
 Grade 2 
alopecia 
 Grade 2 
fatigue 
1,2 
No 
N/A 
N/A 
N/A 
3,4 (if persisting 
despite medical 
treatment) 
Yes 
Toxicity resolves 
to: 
 
Grade <1; 
 
Grade <2 (if 
not considered 
a safety risk 
for the 
subject)  
Resume at next 
lower dose 
Toxicity does not 
resolve within 4 
weeks of last study 
drug administration 
Permanent 
discontinuation 
should be 
considered for any 
severe or life-
threatening event 
Footnotes: †Concurrent elevation of bilirubin > 2x ULN and ALT > 3 x ULN in absence of an evident alternative 
explanation (such as liver mets) will lead to discontinuation of the study drugs 
 
 Complete blood count will be monitored prior to start of study treatment and at the beginning of each 
cycle, as well as on Day 15 of the first two cycles, and as clinically indicated. 
 
6.1.2. Tamoxifen Dose Modifications 
The established clinical dose of tamoxifen (20 mg/day) will be used and no dose modification of tamoxifen 
is planned in this study. 


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For information on tamoxifen and management of tamoxifen related adverse events refer to the Tamoxifen 
SmPC or Prescribing Information. 
 
6.1.3. Goserelin (or equivalent) Dose Modifications 
The established clinical dose of goserelin (3.6 mg subcutaneous injection every 28 days or 10.8 mg 
subcutaneous injection every 12 weeks) may be used and no dose modification of goserelin is planned in 
this study. 
 
For information on goserelin and management of goserelin related adverse events refer to the Zoladex® 
SmPC or Prescribing Information. 
 
The established clinical dose of leuprolide (3.75 mg intramuscular injection every 28 days or 11.25 mg 
intramuscular injection every 12 weeks) may be used and no dose modification of leuprolide is planned in 
this study. 
 
For information on leuprolide and management of leuprolide related adverse events refer to the Lupron® 
SmPC or Prescribing Information. 


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7. STUDY CALENDAR & EVALUATIONS  
[Cycle = 28 days] 
Study Day 
Screening 
Cycle 1 
Cycle 2 
Cycle 3-5 
Every 2 
cycles
Every 3 
cycles
Safety 
follow up
Long-Term 
follow up
-28 
days 
-14 
days 
Day 11 
Day 1 
(±3) 
Day 1 
(±3) 
(± 7) 
 (± 7) 
30 days (±7) 
post last study 
drug 
Every 3 months 
(±14) for 2 years 
from registration 
REQUIRED ASSESSMENTS 
 
Informed Consent/ HIPAA auth. 
X
 
Medical hx including prior therapies; pathology
X
 
Physical examination 
X
X
X
X 
C7+
X
Vital Signs, weight, height (screen only) 
X
X
X
X 
C7+
X
ECOG status 
X
X
X
X 
C7+
X
Baseline signs/ symptoms; AE assessment 
X
X
X
X 
C7+
X5
Concomitant medications 
X
X
X
X 
C7+
X
Survival 
 
X6
LABORATORY TESTS 
 
Blood Chemistries2 
X
X
X
X 
C7+
Platelets, ANC & Hgb3 
X
D1, D15 
D1, D15 
X 
C7+
Pregnancy test for WOCP4 
-72h
X
X
X 
C7+
DISEASE ASSESSMENT7 
 
 
 
 
 
C3-19 
C22+ 
 
 
CT/MRI chest, abdomen/pelvis 
X
 
X8
X8
X
CT or MRI Brain, if clinically indicated 
X
 
Whole body bone scan 
X
 
X8,9
X8,9
Bone x-ray, CT, or MRI10 
X
 
X8
X8
Skin color photography, if applicable 
X
 
X8
X8
TREATMENT EXPOSURE 
 
Palbociclib (Day 1-21) 
X
X
X16 
C7+16
Tamoxifen (Continuous) 
   X
C7+
CORRELATIVE STUDIES (SPECIMEN COLLECTION) 
 
 
 
 
C8, 11, etc. 
 
 
Tumor tissue (unstained slides)11 
X
 
X11
Blood for circulating tumor DNA12  
X
C5 
X12
X12
BANKING SAMPLES (SPECIMEN COLLECTION)
 
Whole Blood13 
X
 
Unstained Slides14 (archival, if available) 
X
 
Serum and Plasma15 
X
 
X
 


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Footnotes: 
 
1: For cycle 1 only: labs do not need to be repeated if done within 7 days of day 1. 
2: Blood Chemistries to include: sodium, potassium, serum creatinine (or GFR; see 3.1.8), calcium, albumin, ALT, AST, bilirubin, alkaline phosphatase. 
3: For Cycles 1 and 2 only, hematology assessments done on Day 1 and also on Day 15  
4: A negative serum or urine pregnancy test is required within 72 hours of study registration and at the beginning of each cycle, if clinically indicated. If the 
urine test cannot be confirmed as negative, a serum pregnancy test will be required.  
5: For subjects with unresolved treatment-related toxicity, follow as medically appropriate until resolution or stabilization 
6: Survival assessment to be recorded every 3 months until 2 years from registration 
7: Appropriate scans to assess disease status will be obtained within 28 days of study enrollment including CT chest, abdomen/pelvis. PET/CT: The CT portion 
of PET/CT is usually of lower quality and should typically not be used in place of dedicated diagnostic CT. However, if the CT portion is of diagnostic quality, 
it may be used.  
8: Disease assessment will be performed on Day 1 of every 2 cycles starting at cycle 3 (ex. Day 1 of cycle 3, 5, 7, etc.) for the first 19 cycles (18 months). 
Disease assessment will be performed on Day 1 of every three cycles starting at cycle 22 (ex. Day 1 of cycle 22, 25, etc.) until discontinuation of study drug.  
9: Bone scan will be repeated as per footnote 8 above only if positive for bone mets at the time of screening or if clinically indicated. 
10: If bone lesion(s) detected from whole body bone scan, perform bone x-ray, CT or MRI of the largest bone metastatic area. 
11: Histological confirmation of breast cancer diagnosis is required (Section 3.1.3). Although not required as a protocol procedure, a patient with a new 
metastatic lesion should be considered for biopsy whenever possible to reassess ER/PR/HER2 status, if clinically indicated. Also, biopsy at the time of 
progression should be considered as clinically indicated, but it is not required as a protocol procedure. If a biopsy is prospectively done as standard of care, 
the study would like to collect samples for correlative research. Unstained slides from either the fresh biopsy or from an archival tumor specimen (metastatic 
lesion) may be submitted at baseline. 
12: Blood for circulating tumor DNA will be collected cycle 1 day 1, cycle 5 day 1 and day 1 of every subsequent 3rd cycle (e.g. cycle 8, 11, etc.), and at 
time of progression. 
13: Submission of whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, labeling and shipping 
instructions. 
14: Submission of unstained slides for banking from an archived FFPE tumor block (if available). See CLM for collection, labeling, and shipping 
instructions. 
15: Submission of serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30 Day Safety Follow up visit. See CLM for 
collection, labeling, processing, and shipping instructions. 
16: After cycle 5, subjects will be assessed every 2 cycles (cycle 7, 9, 11, etc.). Two cycles of palbociclib may be dispensed from cycle 5 onward. 
 


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7.1. 
Screening 
 
7.1.1. Within 28 days prior to registration for protocol therapy  
 Informed consent, HIPAA authorization 
 Medical history including prior therapies and pathology 
 Physical exam, height, weight 
 Vital signs (blood pressure, heart rate, temperature) 
 ECOG performance status 
 Concomitant medications 
 CT/MRI chest, abdomen, pelvis 
 CT or MRI of brain, if clinically indicated 
 Whole body bone scan  
 If bone lesion detected from whole body bone scan, bone X-ray, CT, or MRI of the 
largest bone lesion 
 If skin lesion detected by physical exam, skin color photography 
 
7.1.2. Within 14 days prior to registration for protocol therapy 
 Blood chemistries (sodium, potassium, serum creatinine, calcium, albumin, ALT, AST, 
bilirubin, alkaline phosphatase,) 
 Platelets, ANC and hemoglobin 
 
7.1.3. Within 72 hours prior to registration for protocol therapy  
 Pregnancy test for women of childbearing potential (WOCP). A negative serum or 
urine pregnancy test is required within 72 hours of study registration. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
7.2. 
On Treatment 
 
7.2.1. Day 1 of Cycle 1 
Note: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
 Physical exam, weight 
 Vital signs 
 ECOG performance status 
 Blood chemistries (sodium, potassium, serum creatinine, calcium, albumin, ALT, AST, 
bilirubin, alkaline phosphatase) 
 Platelets, ANC and hemoglobin 
 Pregnancy test for women of childbearing potential (WOCP), if clinically indicated. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 
 Assess adverse events (AE)  
 Concomitant medications 
 Dispense Palbociclib 
 Prescribe Tamoxifen (commercial supply) 


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 Correlative and Banking samples. See CLM for collection, labeling, processing, and 
shipping instructions.  
 
7.2.2. Day 15 of Cycle 1 (±3 days) 
 Platelets, ANC and hemoglobin  
 
7.2.3. Day 1 of Cycle 2 (±3 days) 
 Physical exam, weight 
 Vital signs 
 ECOG performance status 
 Blood chemistries (sodium, potassium, serum creatinine calcium, albumin, ALT, AST, 
bilirubin, alkaline phosphatase) 
 Platelets, ANC and hemoglobin 
 Pregnancy test for women of childbearing potential (WOCP), if clinically indicated. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 
 Assess adverse events 
 Concomitant medications 
 Dispense Palbociclib 
 Prescribe Tamoxifen (commercial supply) 
 
7.2.4. Day 15 of Cycle 2 (±3 days) 
 Platelets, ANC and hemoglobin 
 
7.2.5. Day 1 of Cycle 3-5 (±3 days) 
 Physical exam, weight 
 Vital signs 
 ECOG performance status 
 Blood chemistries (sodium, potassium, serum creatinine calcium, albumin, ALT, AST, 
bilirubin, alkaline phosphatase) 
 Platelets, ANC and hemoglobin 
 Pregnancy test for women of childbearing potential (WOCP), if clinically indicated. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 
 Assess adverse events 
 Concomitant medications 
 Dispense Palbociclib (dispense 2 cycles at cycle 5) 
 Prescribe Tamoxifen (commercial supply) 
 Correlative blood sample: cycle 5 day 1 
 
7.3. 
Every two cycles (±7 days) 
 Disease assessment will be performed every 2 cycles starting at cycle 3 (cycle 3, 5, 7, 
etc.) for the first 19 cycles (18 months): 
o CT/MRI chest, abdomen, pelvis (±7 days). 
o Whole body bone scan if positive for mets at screening or if clinically indicated. 


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o If bone lesion detected from whole body bone scan, repeat bone scan, bone X-ray, 
CT, or MRI of the largest skeletal lesion identified. 
o If skin lesion detected by physical exam at screening, skin color photography. 
 Subjects will be assessed every 2 cycles starting after cycle 5 (cycle 7, 9, 11, etc.): 
o Physical exam, weight 
o Vital signs 
o ECOG performance status 
o Blood chemistries (sodium, potassium, serum creatinine calcium, albumin, ALT, 
AST, bilirubin, alkaline phosphatase) 
o Platelets, ANC and hemoglobin 
o Pregnancy test for women of childbearing potential (WOCP), if clinically 
indicated. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
o Assess adverse events 
o Concomitant medications 
o Dispense 2 cycles of Palbociclib 
o Prescribe Tamoxifen (commercial supply) 
   
7.4. 
Every three cycles (±7 days) 
 Disease assessment will be performed every 3 cycles starting at cycle 22 (cycle 22, 25, 
etc.) until discontinuation of study drug: 
o CT/MRI chest, abdomen, pelvis (±7 days). 
o Whole body bone scan if positive for mets at screening or if clinically indicated. 
o If bone lesion detected from whole body bone scan, repeat bone scan, bone X-ray, 
CT, or MRI of the largest skeletal lesion identified. 
o If skin lesion detected by physical exam at screening, skin color photography. 
 Correlative blood sample: day 1 of every 3rd cycle starting at cycle 8 (cycle 8, 11, etc.) 
 
7.5. 
Off Treatment 
 
7.5.1. Protocol therapy discontinuation 
A subject will be discontinued from the protocol therapy under the following 
circumstances: 
 
If there is evidence of disease progression  
 
If the treating physician thinks a change of therapy would be in the best interest of 
the subject 
 
If the subject requests to discontinue protocol therapy 
 
If the protocol therapy exhibits unacceptable toxicity 
 
If a female subject becomes pregnant  
 
Subjects can stop study participation at any time. However, if they decide to stop, subjects 
will continue to be followed for survival for 24 months after discontinuation.  
 
7.6. 
Safety Follow-up Evaluations 
Subjects discontinued from the treatment phase of the study for any reason will be 
evaluated within 30 days (± 7) of the last dose of study drug. 


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 Physical exam, weight 
 Vital signs 
 ECOG performance status 
 Assess adverse events 
 Concomitant medications 
 Correlative blood samples at the time of progression 
 Optional standard biopsy at the time of progression, with extra passes for research. 
 Banking samples. See Correlative Laboratory Manual for specific instructions. 
 
7.7. 
Long Term Follow-up Evaluations (±14 days) 
 
Subjects will continue to be followed for survival every 3 months for 24 months after 
registration.  
 
 
8. CRITERIA FOR DISEASE EVALUATION 
 
Response assessments for subjects with visceral/ visceral plus bone disease will be made using 
RECIST v1.1. Response assessments for subjects with bone only disease will be made using MDA 
criteria. 
 
8.1. Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 
 
8.1.1. Measurable disease: The presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
 
8.1.1.1. Measurable lesions: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
8.1.1.2. Non-measurable lesions: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 


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8.1.1.3. Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
8.1.1.4. Baseline documentation of “Target” and “Non-Target” lesions:  
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters.  If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
8.2. Response Criteria for Target Lesions –RECIST version 1.1 
 
8.2.1. Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum 
diameters
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions).


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Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study
 
8.2.2. Evaluation of non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
* Complete Response (CR) 
Disappearance of all non-target lesions 
and normalization of tumor marker 
level
* Incomplete Response/ Stable Disease (SD) 
Persistence of one or more non-target 
lesion(s) or/and maintenance of tumor 
marker level above the normal limits
* Progressive Disease (PD) 
Appearance of one or more new lesions 
and/or unequivocal progression of 
existing non-target lesions* 
* Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Sponsor-Investigator. 
 
8.3. Evaluation of best overall response –RECIST version 1.1 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR 
CR
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
CR 
Not evaluated
No
PR 
PR 
Non-PD/ or not all 
evaluated
No 
PR 
SD 
Non-PD or not all evaluated
No
SD 
Not all evaluated 
Non-PD
No
Non-evaluable
PD 
Any
Yes or No
PD 
Any 
PD*
Yes or No
PD 
Any 
Any
Yes
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 


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that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
 
8.4. Definitions for Response Evaluation –RECIST version 1.1 
 
8.4.1. First Documentation of Response: 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.4.2. Confirmation of Response: 
To be assigned a status of complete or partial response, changes in tumor measurements 
must be confirmed by repeat assessments performed no less than four weeks after the 
criteria for response are first met. 
 
8.4.3. Duration of Response: 
Duration of overall response—the period measured from the time that measurement 
criteria are met for complete or partial response (whichever status is recorded first) until 
the date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since treatment 
started). 
 
8.4.4. Duration of Overall Complete Response: 
The period measured from the time that measurement criteria are met for complete 
response until the first date that progressive disease is objectively documented. 
 
8.4.5. Objective response rate:  
The objective response rate is the proportion of all subjects with confirmed PR or CR 
according to RECIST v1.1 from the start of treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the 
start of treatment). 
 
8.4.6. Progression-Free Survival: 
Progression-free survival is defined as the time the treatment is initiated until to the first 
documented progression of disease, as determined per RECIST 1.1 criteria, or death from 
any causes, whichever occurs first. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation.   
 
8.5. Methods of Measurement –RECIST version 1.1 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 28 days before the beginning of the treatment. 
 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. The same 
imaging modality must be used throughout the study to measure disease. 
 


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8.5.1. CT and MRI: 
CT and MRI are the best currently available and most reproducible methods for measuring 
target lesions. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, 
the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with 
breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the 
CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed. 
 
8.5.2. Chest X-Ray: 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by an aerated lung (CT is preferable).   
 
8.5.3. Clinical Examination: 
Clinically detected lesions will only be considered measurable when they are superficial 
(e.g. skin nodules and palpable lymph nodes). For skin lesions, documentation by color 
photography, including a ruler to estimate size of the lesion, is recommended. Photographs 
should be retained at the institution. 
 
8.5.4. Cytology and Histology: 
Cytologic and histologic techniques can be used to differentiate between complete and 
partial responses in rare cases (e.g. after treatment to differentiate residual benign lesions 
and residual malignant lesions in germ cell tumors). Cytologic confirmation of the 
neoplastic nature of any effusion that appears or worsens during treatment is required when 
the measurable tumor has met response or stable disease criteria. 
 


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8.6. Response Criteria for MD Anderson (MDA) Criteria (21) 
Complete Response (CR) 
 Complete sclerotic fill-in of lytic lesions on XR or CT 
 Normalization of bone density on XR or CT 
 Normalization of signal intensity on MRI 

Normalization of tracer uptake on SS 
Partial Response (PR) 
 Development of a sclerotic rim or partial sclerotic fill-in 
of lytic lesions on XR or CT 
 Osteoblastic flare - Interval visualization of lesions with 
sclerotic rims or new sclerotic lesions in the setting of 
other signs of PR and absence of progressive bony 
disease 
 ≥ 50% decrease in measurable lesions on XR, CT, or 
MRI 
 ≥ 50% subjective decrease in the size of ill-defined 
lesions on XR, CT, or MRI 

≥50% subjective decrease in tracer uptake on SS
Progressive Disease (PD) 
 > 25% increase in size of measurable lesions on XR, CT, 
or MRI 
 > 25% subjective increase in the size of ill-defined 
lesions on XR, CT, or MRI 
 > 25% subjective increase in tracer uptake on SS 

New bone metastases
Stable Disease (SD) 
 No change 
 < 25% increase or < 50% decrease in size of measurable 
lesions 
 < 25% subjective increase or < 50% subjective decrease 
in size of ill-defined lesions 

No new bone metastases
Abbreviations: XR: radiography; CT: computed tomography; SS: skeletal scintigraphy; MRI: 
magnetic resonance imaging. 
Measurements are based on the sum of a perpendicular, bi-dimensional measurement of the 
greatest diameters of each individual lesion. 
 
 


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9. BIOLOGICAL CORRELATIVES  
The goal of the correlative objectives are to identify candidate biological mechanisms underlying 
primary and secondary resistance to endocrine therapy combined with CDK 4/6 inhibitors (CDK 
4/6i) using liquid biopsy approaches. Previous work from the PALOMA-3 trial (22) shows that 
approximately 30% of patients treated with endocrine therapy plus palbociclib acquire a driver 
mutation during treatment that may contribute to disease progression, including RB1 aberrations, 
amplification of FGFR and mutations in ESR1 and PIK3CA in circulating tumor DNA (ctDNA). 
However, the majority of tumors do not demonstrate emergence of a characteristic driver mutation 
at the time of progression that is driving resistance to therapy. Therefore, there is a need for 
studies exploring other mechanisms of resistance in clinical specimens. We will conduct a multi-
omics analysis of circulating plasma exosomes isolated from blood samples collected at baseline 
and at the time of disease progression in order to identify candidate mechanisms of resistance to 
the combination of tamoxifen plus palbociclib.  
 
The release of membrane-bound extracellular vesicles (EVs) from cancer cells into body fluids 
like plasma is a tightly regulated mechanism of intracellular communication that involves cell-to-
cell transfer of lipids, proteins, and nucleic acids. This process has been implicated in several 
aspects of cancer-related pathology, including tumor growth, invasion, angiogenesis, and 
metastasis. Emerging evidence suggests that oncogenic mutations in tumors impact EV-mediated 
cell-cell communication, and that EVs shed from tumors contain oncogenic macromolecules (23, 
24). Thus, analyzing EV cargo can shed light on biologic processes ongoing in tumors in response 
to treatment. Exosomes are an abundant form of EVs that are ideally suited for serial analyses in 
patients participating clinical trials since exosomes and their cargo are highly stable in plasma for 
prolonged periods of time and can be readily isolated from frozen plasma samples (25), unlike 
circulating tumor cells. Importantly, analysis of exosomes provides a dynamic and functional read-
out of biological pathways that are activated in cancer cells since exosome cargo includes proteins 
and RNA. This is a significant advantage compared to analysis of ctDNA. For all of these reasons, 
a multi-omics analysis of plasma exosomes isolated from study participants is a promising liquid 
biopsy approach for identifying candidate mechanisms of primary and secondary resistance to 
tamoxifen and palbociclib. 
 
We collected blood samples (6 mL) in Streck tubes on cycle 1 day 1, cycle 5 day 1, and at the time 
of progression. Samples were shipped overnight on the day of collection to the Laboratory of 
Genomic Medicine at the University of Illinois at Chicago. Plasma was isolated immediately on 
arrival and was frozen at -80C° with 48 hours of collection. Plasma exosomes will be isolated 
from frozen specimens using the ExoQuick Exosome Isolation and RNA Purification for future 
RNAseq experiments if additional funding is obtained, and the ExoQuick-ULTRA® for proteomic 
experiments as described below (System Biosciences, Palo Alto, CA).  
 
9.1. Perform proteomic analysis of plasma exosomes to identify potential mechanisms of 
primary and secondary resistance to tamoxifen/palbociclib.  
A collaborator (Y. Gao, PhD, UIC) pioneered single-cell mass spectrometry for proteomic 
analysis of sub-populations of circulating tumor cells. The methods developed in the Gao lab 
have shown that sub-populations of cells could be differentiated at single-cell resolution (26). 
We will not perform single-cell proteomics, but rather we will use this enabling technology to 
perform ultra-sensitive mass spectrometry on the small amount of protein typically isolated 
from exosomes. The single-cell proteomics method developed in the Gao lab combines 


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chemical derivatization, isotopologue labeling, advanced statistical modeling and optimized 
sample preparation to sample ultra-low protein concentrations in a sensitive and quantitative 
manner. This newly developed chemical derivatization method is able to enhance peptide 
ionization by 10-20 fold. The isotopologue labeling approach allows analysis of multiple 
samples in parallel. Statistical sampling allows further extension of the resolving power 
beyond instrument limitations. Finally, optimized sample preparation ensures minimal sample 
loss.  
 
To compare the protein contents of exosomes, total exosome will be first extracted from each 
plasma sample as previously described (27, 28). Once separated, the exosome from each 
sample will be labeled with Tandem Mass Tag (TMT) isobaric tags for quantitative mass 
spectrometry (MS) analysis. Exosomes obtained from each patient prior to treatment will be 
measured three times in three independent experiments as technical replicates. To improve 
the detection and quantitation of low abundant exosome proteins, we will use existing 
exosome proteomics data and ExoCarta (http://www.exocarta.org/) to guide our analysis. 
Specifically, an inclusion list will be generated to include all the known exosome protein-
derived peptides, as well as proteins that belong to candidate resistance mechanisms (e.g. 
Cdk2, cyclin E, Rb, and other cell cycle regulatory proteins and proteins involved in ER 
signaling). We will also guide the mass spectrometer to aim for these ions as specific 
retention time points. This type of experiment is similar to multiple reaction monitoring 
(MRM), which is highly sensitive and reproducible. After mass spectrometry analysis, all the 
data will be analyzed and quantified using ProLuCID (29) and Census (30) to generate a 
complete exosome protein identification and quantitation data set. We will then analyze the 
data to identify key proteins and pathways that contribute to the differences between 
responders and non-responders in pre-treatment samples. This will provide insight into 
possible mechanisms of primary resistance.  For the responders, we will also compare the 
exosome proteome at baseline vs. at the time of progression. This will provide insight into 
potential mechanisms responsible for secondary (i.e. acquired) resistance to CDK 4/6i. 
For both analyses, we will, in addition, correlate with the primary outcome PFS. 
 
Protein clusters that persistently change together will be subject to pathway analysis using 
STRING database (http://www.string-db.org/). With both the proteomics data and 
transcriptomics data, we will perform a multi-omics data integration to find the correlation 
between the proteome and the transcriptome. We have previously shown that such analysis 
could greatly improve the quality and confidence of the results (26). 
 
9.2.  Analyze tumor specimens for protein expression of candidate markers of primary 
resistance.  
In order to confirm potential biomarkers of primary resistance identified with the multi-omics 
analysis of plasma exosomes, we will analyze pre-treatment tumor specimens using a 
multiplex immunofluorescence (IF) tissue imaging system. We will use a multiplex 
immunofluorescence (IF) staining assay and automated digital image analysis with the Vectra 
3® automated quantitative pathology imaging system (Perkin-Elmer, Waltham, MA) to 
assess the extent of protein staining in tumor cells for up to 5 proteins of interest. 
Optimization of antibody staining with commercially available antibodies, tumor staining, 
image analysis and quantification of protein staining will be conducted by the Research 
Histology and Tissue Imaging Core (RHTIC) in the Research Resources Center (RRC) at the 


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University of Illinois at Chicago in collaboration with the study pathologist. The multiplex 
antibody panel will include a pan-cytokeratin antibody that will allow us to distinguish tumor 
cells from the stromal compartment, and DAPI to identify membrane staining. Stains will be 
optimized using Opal® reagents (PerkinElmer). Slides will be scanned on a Vectra 3® 
multispectral imaging system for whole-slide image analysis. Machine learning algorithms 
will isolate epithelium and stroma, and all images will be reviewed by the study pathologist 
(Wiley) to confirm the accuracy of cellular compartment segmentation. Quantification of 
protein staining in digitized images will be accomplished using algorithms that generate a 
normalized, log2 transformed staining intensity for each protein. T-tests will compare staining 
intensity in responders vs. non-responders. Cox model will be used to correlate staining 
intensity with PFS. 
 
9.3. Compare differences in response for subjects presenting with de novo metastatic breast 
cancer to subjects that progressed while on aromatase inhibitors. 
There will be two main subject populations in this trial: subjects that present with de novo 
metastatic disease and subjects that will progress while on adjuvant endocrine therapy with 
aromatase inhibitors. Looking at differences in response between these 2 groups could 
provide further information about the mechanism for endocrine resistance. 
 
9.4. Compare differences in response and toxicity profile in African American and Hispanic 
subjects to Caucasian subjects. 
Minorities are underrepresented in clinical trials. Obtaining more information about possible 
differences in response to therapy is important to better the biology. Many African American 
subjects will have a baseline low neutrophil count. Observing the toxicity profile of 
palbociclib in this population may provide guidance for further monitoring while on therapy 
and supportive care. 
 
9.5. Banking of Leftover Biospecimens 
Subject consent will be obtained to bank any leftover samples that were collected for study-
specific correlative research. Hoosier Cancer Research Network (HCRN), as Administrative 
Headquarters for the Big Ten CRC, will manage the banked samples. Samples will be banked 
indefinitely in the Hoosier Cancer Research Network Biorepository and used for future 
unspecified cancer-related research. 
 
9.6. Banking Samples for Future Unspecified Research  
Subject consent will be obtained for additional samples collected for future Big Ten Cancer 
Research Consortium studies. HCRN will manage the banked samples. Samples will be 
banked indefinitely in the HCRN Biorepository.  
This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to 
treatment on Cycle 1 Day 1 and at End of Treatment.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment 
on Cycle 1 Day 1 and at End of Treatment. 
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin 
fixed paraffin embedded tumor sample.  


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Please refer to the Correlative Laboratory Manual for all sample collection, processing, 
labeling, and shipping instructions. 
 
10. DRUG INFORMATION  
 
10.1. Drug Name 
IBRANCE® (palbociclib) 
 
Classification 
Kinase inhibitor. 
 
Mechanism of Action 
Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and 
CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, 
palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer 
cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. 
 
How Supplied 
Palbociclib is supplied in the bottles of 21 capsules of the following strengths: 125 mg 
(NDC 0069-0189-21), 100 mg (NDC 0069-0188-21), and 75 mg (NDC 0069-0187-21). 
 
Availability 
Pfizer will supply palbociclib at no charge to subjects participating in this clinical trial.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Storage, Handling, and Accountability 
Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F 
to 86 °F). 
 
Description 
125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed 
with white ink "Pfizer" on the cap, "PBC 125" on the body. 100 mg capsules: opaque hard 
gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink 
"Pfizer" on the cap, "PBC 100" on the body. 75 mg capsules: opaque hard gelatin capsules, 
size 2, with light orange cap and body, printed with white ink "Pfizer" on the cap, "PBC 75" 
on the body. 
 
Administration 
Palbociclib should be taken with food in combination with tamoxifen on days 1-21 of the 
28-day cycle once daily. Subjects should be encouraged to take their dose at approximately 
the same time each day. 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. See Section 5.3.2 for missed doses.  


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Risks 
Most common adverse reactions (incidence ≥10%) were neutropenia, leukopenia, fatigue, 
anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, 
thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and 
epistaxis. 
 
Warnings and Precautions 
Please refer to the package insert or Investigator’s Brochure for a complete list of adverse 
events. 
 
Neutropenia 
Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-2) 
with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%. A Grade 
≥3 decrease in neutrophil counts was reported in 66% of patients receiving palbociclib 
plus letrozole in Study 1 and 66% of patients receiving palbociclib plus fulvestrant in 
Study 2. In Study 1 and 2, the median time to first episode of any grade neutropenia was 
15 days and the median duration of Grade ≥3 neutropenia was 7 days.  
Febrile neutropenia has been reported in 1.8% of patients exposed to palbociclib across 
Studies 1 and 2. One death due to neutropenic sepsis was observed in Study 2. Physicians 
should inform patients to promptly report any episodes of fever.  
 
Pulmonary Embolism 
Pulmonary embolism was reported in 15/872 (1.7%) of palbociclib treated patients in Study 
A5481003, A5481008, and A5481023, and in 5/471 (1.1%) of patients treated in the 
comparator arms of these studies. These incidences are consistent with epidemiological data 
on the frequency of pulmonary embolism in the advanced breast cancer population, and the 
higher incidence for pulmonary embolism in the palbociclib treated patients may be 
explained by the increased median treatment duration on the palbociclib arms of these 
studies. Pulmonary embolism and other venous thromboembolic events will continue to be 
monitored but are not currently considered to be adverse drug reactions of palbociclib. 
 
Effects on the Gastrointestinal Tract 
Non-adverse palbociclib-related gastrointestinal (GI) tract findings were noted in 
nonclinical toxicity studies. Treatment-related GI tract events have been commonly 
observed in patients who receive palbociclib as a single agent or in combination with other 
anticancer therapies. The most frequent gastrointestinal treatment-related events were 
Nausea, Vomiting, Diarrhea, and Decreased appetite. Most occurrences were mild (Grade 
1). 
 
Embryo-Fetal Toxicity 
Based on findings in animals and mechanism of action, palbociclib can cause fetal harm. 
Palbociclib caused embryo-fetal toxicities in rats and rabbits at maternal exposures that 
were greater than or equal to 4 times the human clinical exposure based on area under the 
curve (AUC). Advise females of reproductive potential to use effective contraception 
during therapy with palbociclib and for at least 120 days after the last dose of study drug. 


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Effects on Testes 
Palbociclib caused testicular degeneration in rats and dogs. The incidence and severity was 
dose related and correlated with decreases in testicular weight in the rat. Reversibility of the 
testicular degeneration was demonstrated following a 12-week non-dosing period in rats 
and dogs (also following a 4-week recovery period in rats). Patients should consider sperm 
preservation prior to beginning therapy with palbociclib. 
 
Male patients must be surgically sterile or must agree to use effective contraception during 
the therapy and for at least 120 days after the last dose of study drug. 
 
 


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10.2. Drug Name 
Tamoxifen (Nolvadex®) 
 
Classification 
Nonsteroidal antiestrogen. 
 
Mechanism of Action 
Tamoxifen citrate is a nonsteroidal agent that has demonstrated potent antiestrogenic 
properties in animal test systems. The antiestrogenic effects may be related to its ability to 
compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits 
the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and 
causes the regression of already established DMBA-induced tumors. In this rat model, 
tamoxifen appears to exert its antitumor effects by binding the estrogen receptors. 
In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol 
for estrogen receptor protein. 
  
How Supplied 
20 mg Tamoxifen Citrate Tablets, USP are available containing tamoxifen as the citrate in 
an amount equivalent to 20 mg of tamoxifen. They are available as follows: bottles of 30 
tablets (NDC 0378-0274-93), bottles of 100 tablets (NDC 0378-0274-01), and bottles of 
250 tablets (NDC 0378-0274-25).  
 
Availability 
Commercial supplies of tamoxifen will be used in this study and billed to third party payers 
or the subject.   
 
Storage, Handling, and Accountability 
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Avoid 
excessive heat (over 104°F/40°C). Protect from light. Dispense in a tight, light-resistant 
container as defined in the USP using a child-resistant closure 
 
Description 
Twenty- mg tamoxifen tablets are white to off-white, unscored, round tablets debossed with 
M on one side of the tablet and 274 on the other side. 
 
Administration 
Tamoxifen can be taken with or without food on each day of the 28-day cycle once daily. 
Subjects should be encouraged to take their dose at approximately the same time each day.  
 
Risks: 
 
General 
In general, hot flashes, nausea, and vomiting have been the most commonly reported 
adverse effects, occurring in up to 25% of subjects. 
Less common but serious side effects are:  
 Risk of blood clots, especially in the lungs and legs 


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 Stroke 
 Cataracts 
 Endometrial and uterine cancers 
 Bone loss in premenopausal women 
 Mood swings, depression, and loss of libido 
 
10.3. Drug Name 
Zoladex® (Goserelin acetate implant) 
 
Classification 
Luteinizing hormone releasing hormone (LHRH) agonist 
 
Mechanism of Action 
Goserelin is a synthetic decapeptide analogue of GnRH. Goserelin acts as an inhibitor of 
pituitary gonadotropin secretion when administered in the biodegradable formulation. In 
animal and in vitro studies, administration of goserelin resulted in the regression or 
inhibition of growth of the hormonally sensitive dimethylbenzanthracene (DMBA)-induced 
rat mammary tumor and Dunning R3327 prostate tumor. 
 
How Supplied 
Goserelin is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids 
copolymer (13.3-14.3 mg/dose) impregnated with goserelin acetate equivalent to 3.6 mg of 
goserelin in a disposable syringe device fitted with a 16-gauge x 36 +/- 0.5 mm siliconized 
hypodermic needle with protective needle sleeve [SafeSystem™ Syringe] (NDC 0310-
0950-36). The unit is sterile and comes in a sealed, light- and moisture-proof, aluminum foil 
laminate pouch containing a desiccant capsule. 
 
Availability 
Commercial supplies of goserelin will be used in this study and billed to third party payers 
or the subject. 
 
Storage, Handling, and Accountability 
Store at room temperature (do not exceed 25°C [77°F]) 
 
Administration 
Goserelin, at a dose of 3.6 mg, should be administered subcutaneously on day 1 of each 
cycle into the anterior abdominal wall below the navel line using an aseptic technique by 
qualified medical personnel. 
 
Risks 
Hot flashes (flushing), dizziness, headache, increased sweating, decreased libido, trouble 
sleeping, nausea, change in breast size, hair loss, or mental/mood changes (such as 
depression, mood swings, hallucinations) may occur. Pain, bruising, bleeding, redness, or 
swelling at the injection site may also occur. In women, vaginal dryness may also occur. 
 
 


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10.4. Drug Name 
Lupron® (leuprolide acetate) 
 
Classification 
Luteinizing hormone releasing hormone (LHRH) agonist 
 
Mechanism of Action 
Leuprolide acetate is a synthetic nonapeptide analogue of GnRH.  Leuprolide acetate is a 
long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg results 
in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins. 
 
How Supplied 
Each syringe contains sterile lyophilized microspheres, which is leuprolide incorporated in a 
biodegradable copolymer of lactic and glycolic acids.  
 
Availability 
Commercial supplies of leuprolide will be used in this study and billed to third party payers 
or the subject. 
 
Storage, Handling, and Accountability 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) 
 
Administration 
Leuprolide, at a dose of 3.75 mg, should be administered intramuscularly on day 1 of each 
cycle into the gluteal area, anterior thigh, or deltoid; injection sites should be alternated.  
using an aseptic technique by qualified medical personnel. 
 
Risks 
Estradiol levels may increase during the first weeks following the initial injection of 
leuprolide, but then decline to menopausal levels. This transient increase in estradiol can be 
associated with a temporary worsening of signs and symptoms.  
 
As would be expected with a drug that lowers serum estradiol levels, the most frequently 
reported adverse reactions were those related to hypoestrogenism. Adverse events occurring 
in clinical studies with LUPRON DEPOT that are associated with hypoestrogenism include: 
hot flashes, headaches, emotional lability, decreased libido, acne, myalgia, reduction in 
breast size, and vaginal dryness. Patients should be counseled on the possibility of the 
development or worsening of depression and the occurrence of memory disorders.  
 
The induced hypoestrogenic state also results in a loss in bone density over the course of 
treatment, some of which may not be reversible.  
 
Pain, bruising, bleeding, redness, or swelling at the injection site may also occur.  
 
 


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11. ADVERSE EVENTS  
 
11.1. Definitions of Adverse Events 
 
11.1.1. Adverse Event (AE): 
An AE is any unfavorable and unintended medical occurrence during the course of the 
study whether or not considered related to the study therapy. The following are examples 
of AEs:  
 A sign (including an abnormal laboratory finding) or symptom 
 A disease temporally associated with participation in an investigational study 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of 
an AE (e.g., surgical insertion of central line) should not be recorded as an AE. Disease 
progression should not be recorded as an AE, unless it is attributable by the site 
investigator to the study therapy. 
 
11.1.2. Serious Adverse Event (SAE): 
A SAE is an adverse event that: 
 Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified 
procedures such as administration of chemotherapy, central line insertion, metastasis 
interventional therapy, resection of primary tumor, or elective surgery, will not be 
considered serious adverse events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed 
in the definition above). Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions not resulting in hospitalization; or the development of drug 
dependency or drug abuse. 
o Palbociclib overdose. For purposes of this trial, an overdose will be defined as any 
dose exceeding the prescribed dose for palbociclib by 20% over the prescribed 
dose. 
 
11.1.3. Unexpected Adverse Event: 
For this study, an AE is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current Investigator’s Brochure (IB), 


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prescribing information or when it is not included in the informed consent document as a 
potential risk. Unexpected also refers to AEs that are mentioned in the IB as occurring with 
a class of drugs or are anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under investigation. 
 
11.1.4. Causality  
AEs will be categorized according to the likelihood that they are related to the study 
drug(s). Specifically, they will be categorized using the following terms:  
 
Unrelated 
The Adverse Event is clearly not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
 
11.2. Adverse Event (AE) Reporting 
 Adverse events (AEs) will be recorded from the time of consent and for at least 30 days 
after last dose of study drug. 
 AEs will be recorded regardless of whether or not the event(s) are considered related to 
trial medications.  
 All AEs considered related to trial medication will be followed until resolution, return 
to baseline or ≤ Grade 1, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever is earlier 
 
11.3. Reporting of Pregnancy 
Although pregnancy is not considered an adverse event, it is the responsibility of 
investigators or their designees to report any pregnancy in a subject (spontaneously 
reported to them) that occurs during the trial or within 120 days of last dose of study drug. 
All subjects who become pregnant must be followed to the completion/termination of the 
pregnancy. All pregnancies must be reported within 1 business day to BTCRC AHQ on the 
Pregnancy Report form (See Documents/Info tab of the EDC).  
 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the 
outcome (health of infant) must also be reported. Such events must be reported within 1 
business day to BTCRC AHQ. BTCRC AHQ will report the event within 1 business day to 
Pfizer Global Safety (Attn: Worldwide Product Safety; FAX 1-866-997-8322). 
 
11.4. Serious Adverse Event (SAE) Reporting 
 
11.4.1. Study Center (Site) Requirements for Reporting SAEs: 
 SAEs caused by a protocol-mandated intervention occurring after informed consent but 
prior to initiation of study therapy will be recorded (e.g. SAEs related to invasive 
procedures such as biopsies or medication washout).  


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 SAEs that occur on or after initiation of study therapy until 90 days after last dose of 
study therapy or until a new anti-cancer treatment starts, whichever occurs first, will be 
reported within 1 business day of discovery of the event.   
 SAEs include events related and unrelated to the study therapy.  
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ 
Grade 1 or baseline and/or deemed clinically insignificant and/or until a new anti-
cancer treatment starts, whichever occurs first. 
 For any pregnancy SAE, the site investigator will follow the female subject until 
completion of the pregnancy, and must document the outcome of the pregnancy (either 
normal or abnormal outcome). If the outcome of the pregnancy was abnormal (e.g., 
spontaneous or therapeutic abortion), the site investigator should report the abnormal 
outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must 
be reported as an SAE. This information will be reported on the Pregnancy Form. 
 
The completed SAE Submission Form (see Documents/Info tab of the EDC) must 
be sent to Big Ten Cancer Research Consortium (BTCRC) Administrative 
Headquarters (AHQ) within 1 business day of discovery of the event. The form must 
be sent electronically to safety@hoosiercancer.org. The site investigator is responsible 
for informing the IRB and/or other local regulatory bodies of the SAE as per local 
requirements. 
 
The original copy of the SAE Submission Form and the e-mail correspondence must be 
kept within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed in 11.2.2.1), sites must 
submit a follow up SAE Submission Form within a reasonable timeframe to BTCRC 
AHQ at safety@hoosiercancer.org. 
 
11.4.2. BTCRC AHQ Requirements for Reporting SAEs to Pfizer: 
BTCRC AHQ will submit all SAEs (e.g. SAEs, overdose, pregnancy, etc.) received from 
sites to Pfizer within one business day of receipt of the SAE Submission Form. BTCRC 
AHQ will provide follow-up information to Pfizer as it is received from participating site 
or within one business day. 
 
BTCRC AHQ will fax SAE Submission Form for all SAE reports and any other 
relevant safety information to Pfizer Global Safety (Attn: Worldwide Product Safety) 
at: 
Facsimile number:  1-866-997-8322 
 
11.4.3. Sponsor-Investigator Responsibilities 
BTCRC AHQ will send a SAE summary to the sponsor-investigator within 1 business 
day of receipt of SAE Submission Form from a site.  The sponsor-investigator will 
promptly review the SAE summary and assess for expectedness and relatedness. 
 
11.4.4. BTCRC AHQ Responsibilities to FDA 
The FDA has concluded this protocol is exempt from the requirements of an IND. BTCRC 
AHQ will continue to facilitate compliance of applicable requirements for the sponsor-


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investigator in relation to this study. This includes but is not limited to 21 CFR 50.20 
informed consent, 21 CFR Part 56 IRB, and pertinent sections of the Public Health Service 
Act and FDAAA. 
 
IND Safety Reports Unrelated to this Trial 
Pfizer will send IND safety reports from external studies that involve the study drug to 
BTCRC AHQ at (safety@hoosiercancer.org). BTCRC AHQ will forward safety reports to 
the sponsor-investigator who will review these reports and determine if revisions are 
needed to the protocol or consent. BTCRC AHQ will forward these reports to participating 
sites within 1 business day of receiving the sponsor-investigator’s review. Based on the 
sponsor-investigator’s review, applicable changes will be made to the protocol and 
informed consent document (if required).  All IND safety reports will also be made 
available to sites via OnCore®.    
 
Upon receipt from BTCRC AHQ, site investigators (or designees) are responsible for 
submitting these safety reports to their respective IRBs, as per their IRB policies. 
 
12. STATISTICAL CONSIDERATIONS 
12.1. Study Design 
This is a non-randomized, open-label, multicenter, phase II study of palbociclib in 
combination with tamoxifen in subjects with HR(+)/HER2(-) advanced breast cancer who 
have not received prior systemic anti-cancer therapies for their advanced/metastatic 
disease. Palbociclib is taken orally with food at a dose of 125 mg on days 1-21 of each 28-
day cycle. Tamoxifen is taken orally at a dose of 20 mg on days 1-28 of the 28-day cycle 
(i.e., continuously). Treatment will continue until disease progression, unacceptable 
toxicity, or subject refusal. 
 
It is planned that the data from all centers participating in the trial will be combined, so 
that an adequate number of subject are available for analysis.  
 
12.2. Analysis Datasets 
 
Methods of Statistical Analysis 
The definitions of the study populations are listed below. The appropriate study population for 
each analysis should be chosen and defined in the protocol. 
 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study.  
Evaluable 
This will comprise all subjects who receive at least one cycle 
of trial drug and either undergo at least one post-baseline 
assessment or die before any evaluation.  
Safety 
This will comprise all subjects who received at least a single 
dose of study drug.  
 


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12.3. Sample Size 
Study endpoint is progression free survival (PFS) as assessed by RECIST v1.1 criteria). 
Previous studies (31, 32) identified progression free survival with tamoxifen of 13 months 
in pre-menopausal women and 14.5 months in post-menopausal women in first line 
treatment for breast cancer. We use a null hypothesis of median PFS 15 months as a 
conservative choice and the alternative hypothesis of median PFS 25 months (31, 32). 
Controlling for a probability of one-sided Type I error of 0.05, the proposed sample size will 
be 48 to achieve an 80% statistical power for detecting this difference, assuming 20% 
censoring rate due to unevaluable, drop-out, and other lost-to-follow-up. The sample size 
analysis was conducted using the software PASS 14 (NCSS, Kaysville, Utah, USA.). The 
test was based on an exponential distribution assumption for single arm studies. The accrual 
period was assumed to be 24 months and the maximum follow-up 24 months too.  
 
12.4. Analysis of Primary Objectives/Aims 
The primary objective of the Phase II study is to estimate the activity of the combination of 
palbociclib and tamoxifen in first line therapy for subjects with HR(+)/HER2(-) advanced 
breast cancer who have not received prior systemic anti-cancer therapies for their 
advanced/metastatic disease, evaluated by progression-free survival (PFS) using RECIST 
1.1 in subjects with HR(+)/HER2(-) advanced breast cancer who have not received prior 
systemic anti-cancer therapies for their advanced/metastatic disease treated with palbociclib 
in combination with tamoxifen. Median PFS times will be computed, and PFS rate will be 
calculated with associated 95% confidence intervals. Kaplan-Meier curves will be plotted. 
Data will be analyzed using the PROC FREQ and PROC LIFETEST in SAS. 
 
12.5. Analysis of Secondary Endpoints 
Characterize safety and tolerability of palbociclib and tamoxifen in first line therapy for 
subjects with HR(+)/HER2(-) advanced breast cancer who have not received prior systemic 
anti-cancer therapies for their advanced/metastatic disease. 
 Proportion of subjects with each grade of adverse events as defined by CTCAE v4 will 
be computed along with 95% confidence intervals, and reported in a tabular and 
descriptive manner. 
 
Assess response rate based on RECIST 1.1 or MDA Criteria. The response rate (complete 
or partial response) and 95% confidence interval for the response rate will be computed using 
PROC FREQ in SAS (Cary, NC).  
 
Evaluate clinical benefit rate RR (complete, partial response, or stable disease) based on 
RECIST 1.1 or MDA Criteria in subjects with HR(+)/HER2(-) advanced breast cancer who 
have not received prior systemic anti-cancer therapies for their advanced/metastatic disease 
treated with palbociclib in combination with tamoxifen. 
 Clinical benefit rate (complete, partial response, or stable disease) will be assessed every 
8 weeks +/- 1 week while on study treatment using RECIST 1.1 (section 8) or MDA 
Criteria (for patients with bone only disease). Response will be recorded as disease 
control rate (DCR), or stable disease plus partial response plus complete response, and 
reported via waterfall plot. The response rate and 95% confidence interval for the 
response rate will be computed using PROC FREQ in SAS (Cary, NC). 


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Measure 2-year overall survival (OS) in subjects with HR(+)/HER2(-) advanced breast 
cancer who have not received prior systemic anti-cancer therapies for their 
advanced/metastatic disease treated with palbociclib in combination with tamoxifen. 
 Median OS times will be computed, and OS rate will be calculated with associated 95% 
confidence intervals. Kaplan-Meier curves will be plotted. Data will be analyzed using 
the PROC FREQ and PROC LIFETEST in SAS.  
 
12.6. Analysis of Correlative Endpoints, if funding is secured 
 Perform proteomic analysis of plasma exosomes to identify potential mechanisms of 
primary and secondary resistance to tamoxifen/palbociclib. 
 Analyze tumor specimens for protein expression of candidate markers of primary 
resistance. 
 Compare difference in response for subjects presenting with de novo metastatic breast 
cancer to subjects that progressed while on aromatase inhibitors 
 Compare differences in response and toxicity profile in African American and Hispanic 
subjects to Caucasian subjects 
 Compare differences in response and toxicity profile between pre- and post-
menopausal women. 
 
13. TRIAL MANAGEMENT 
 
13.1. Study Monitoring 
Monitoring visits to the trial sites will be made periodically during the trial to ensure key 
aspects of the protocol are followed. For-cause visits may occur as necessary. Source 
documents will be reviewed for verification of agreement with data entered into OnCore®. 
It is important for the site investigator and their relevant personnel to be available for a 
sufficient amount of time during the monitoring visits or audit, if applicable. The site 
investigator and institution guarantee access to source documents by BTCRC AHQ or its 
designee. 
 
Remote validation of Oncore® data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the 
EDC system and transmitted to the site to address in a timely fashion. Corrections will be 
made by the study site personnel.  
 
The trial site may also be subject to quality assurance audit by Pfizer or its designee as well 
as inspection by appropriate regulatory agencies. 
 
13.2. Data and Safety Monitoring Plan 
The study will be conducted in accordance with the University of Illinois Cancer Center’s 
Data and Safety Monitoring Plan. The University of Illinois Cancer Center Data Safety 
Monitoring Committee (DSMC) will review and make recommendations on this trial. 
BTCRC AHQ will provide the University of Illinois Cancer Center DSMC with periodic 
data reports to comply with the UICC DSMC review requirements. 
 
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 
Review of all adverse events requiring expedited reporting as defined in the protocol 
 
Notify participating sites of adverse events requiring expedited reporting 
 
Provide the Sponsor Investigator with trial accrual progress and safety 
information  
 
Provide data summary reports to the sponsor-investigator  
 
Provide data summary reports to the lead institution’s Data Safety Monitoring 
Committee for review as per their DSMP. 
 
Data and Safety Monitoring and Reporting Guidelines 
BTCRC AHQ will compile data summary reports for this trial and submit these reports 
monthly to the Sponsor Investigator. BTCRC AHQ will submit data summary reports at 
minimum twice per year for review by the University of Illinois Cancer Center Data Safety 
Monitoring Committee (DSMC).  
 
13.3. Amendments 
If it is necessary for the study protocol to be amended and/or the informed consent revised, 
the amendment or a new version of the study protocol (amended protocol) and/or the 
revised informed consent will be generated by BTCRC AHQ and must be approved by the 
sponsor-investigator, Pfizer (if required by the contract), the FDA (if applicable), and each 
site’s IRB.  
 
The site investigator is responsible for the distribution of these documents to his or her 
IRB, and to the staff at his or her center. 
 
13.4. Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator 
of the trial is solely responsible for determining whether the trial and its results are subject 
to the requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov. The sponsor-investigator has delegated responsibility to 
BTCRC AHQ for registering the trial and posting the results on clinicaltrials.gov. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information. 
 
 


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14. DATA HANDLING AND RECORD KEEPING 
 
14.1. Data Management 
BTCRC AHQ will serve as the Clinical Research Office for this trial. Data will be 
collected through a web based clinical research platform, OnCore®, a system compliant 
with Good Clinical Practices and Federal Rules and Regulations. BTCRC AHQ personnel 
will coordinate and manage data for quality control assurance and integrity. All data will 
be collected and entered into OnCore® by study site personnel from participating 
institutions.   
 
14.2. Case Report Forms and Submission 
Generally, clinical data will be electronically captured in OnCore® and correlative results 
will be captured in OnCore® or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the 
source document. Select standard of care data will also be captured in OnCore®, according 
to study-specific objectives. Please see the Data and Safety Oversight Process (DSOP) 
guidelines for further details.  
 
The completed dataset is housed at BTCRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, 
except for authorized representatives of appropriate Health/Regulatory Authorities, without 
written permission from the sponsor-investigator and BTCRC AHQ. After the initial 
publication, the complete data set will be available to all BTCRC institutions. 
 
14.3. Record Retention 
To enable evaluations and/or audits from Health Authorities/BTCRC AHQ, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records; e.g., hospital records), all original signed informed 
consent forms, copies of all source documents, and detailed records of drug disposition. 
All source documents are to remain in the subject’s file and retained by the site 
investigator in compliance with local and federal regulations. 
 
14.4. Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records 
identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. Information 
collected will be maintained on secure, password protected electronic systems. Paper files 
that contain personal information will be kept in locked and secure locations only 
accessible to the study site personnel.  
 
Samples that are collected will be identified by a subject’s study number assigned at the 
time of registration to the trial. Any material issued to collaborating researchers will be 
anonymized and only identified by the subject study number. 
 
Subjects will be informed in writing that some organizations including the sponsor-
investigator and his/her research associates, BTCRC AHQ, Pfizer, IRB, or government 
agencies, like the FDA, may inspect their medical records to verify the information 


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collected, and that all personal information made available for inspection will be handled 
in strictest confidence and in accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15. ETHICS 
 
15.1. Institutional Review Board (IRB) Approval 
The final study protocol, including the final version of the Written Informed Consent 
Form, must be approved or given a favorable opinion in writing by an IRB. The 
investigator must submit written approval to the BTCRC AHQ office before he or she can 
enroll any subject into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the 
IRB annually, as local regulations require.  
 
Progress reports and notifications of serious and unexpected adverse events will be 
provided to the IRB according to local regulations and guidelines. 
 
15.2. Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH Good Clinical Practice, and 
applicable regulatory requirements. 
 
15.3. Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects 
must also be notified they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. 
 
 


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