Conditions: Breast Cancer Stage IV Unresectable Locally Advanced Invasive Breast Cancer Metastatic Invasive Breast Cancer
Keywords: Unresectable locally advanced invasive breast cancer Metastatic invasive breast cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
This research study is studying a drug called Palbociclib in combination with Bazedoxifene (a type of endocrine therapy, which prevents breast cancer cell growth by blocking estrogen stimulation) as a possible treatment for this diagnosis.

The names of the study interventions involved in this study are:

* Palbociclib
* Bazedoxifene

Detailed description:
This research study is a Phase I/II clinical trial. Phase II clinical trial tests the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. It also means that the FDA (the U.S. Food and Drug Administration) has not yet approved Palbociclib in combination with Bazedoxifene for use in participants with your type of cancer, but it has been approved for other uses (metastatic breast cancer).

Palbociclib is a drug that may stop cancer cells from growing. Palbociclib blocks activity of two closely related enzymes (proteins that help chemical reactions in the body occur), called Cyclin D Kinases 4 and 6 (CDK 4/6). These proteins are part of a pathway, or a sequence of steps which is known to control cell growth. Laboratory testing has shown that palbociclib may stop the growth of hormone receptor positive breast cancer.

Endocrine therapy prevents breast cancer cell growth by blocking the activity of the estrogen receptor. During this study the endocrine therapy will be bazedoxifene.

In this research study, the investigators are evaluating how safe palbociclib is and how well palbociclib in combination with bazedoxifene, a form of endocrine treatment, works in participants with a history of stage four breast cancer.

Arms:
arm 1: Palbociclib 125 mg Oral on days 1-21 per cycle Bazedoxifene 40 mg Oral on days 1-28 per cycle

One cycle is 28 days.

Interventions: intervention 1: Palbociclib intervention 2: Bazedoxifene
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
Title: A Phase Ib/II Study of Palbociclib in Combination with Bazedoxifene in Hormone Receptor Positive 
Breast Cancer 
 
NCT Number: NCT02448771 
 
IRB Approval Date: 04/23/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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DF/HCC Protocol #: 15-060 
 
DF/HCC Biomedical Protocol Template: November 11, 2014 
 
TITLE:  A Phase Ib/II Study of Palbociclib in Combination with Bazedoxifene in Hormone Receptor Positive 
Breast Cancer 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
 
*Principal Investigator (PI): 
Rinath Jeselsohn M.D. 
 
Breast Oncology Center 
 
Dana Farber Cancer Institute                                                       
 
450 Brookline Ave, Boston MA 02215  
 
Tel: 617-632-3800 
 
 
Fax: 617-632-1980 
 
 
Email: rinath_jeselsohn@dfci.harvard.edu 
 
 
 
Other Investigators: 
Eric Winer M.D.  
Breast Oncology Center                                                    
Dana Farber Cancer Institute 
450 Brookline Ave, Boston MA 02215 
Tel: 617-632-3800 
Fax: 617-632-1930 
Email: ewiner@partners.org 
 
Myles Brown M.D. 
Dana Farber Cancer Institute 
450 Brookline Ave, Boston MA 02215 
Tel: 617-632-3948 
Fax: 617-632-5417 
Email: myles_brown@dfci.harvard.edu 
 
 
Ian Krop, M.D., Ph.D.  
Dana-Farber Cancer Institute  
450 Brookline Ave, Boston, MA 02215  
Tel: 617-632-6973  
Fax: 617-632-1930  
Email: ian_krop@dfci.harvard.edu 
                               
Nancy U. Lin, M.D.  
Breast Oncology Center 
Dana-Farber Cancer Institute  
450 Brookline Ave, Boston, MA 02215 
Tel: 617-632-2335  
Fax: 617-632-1930  
Email: nlin@partners 
 


 
 
 
Page | 3  
 
Matthew J. Ellis M.D., Ph.D. 
Washington University St. Louis  
660 South Euclid Avenue, Campus Box 8069 
St. Louis, MO 63110.  
Tel: 314-362-3774 
Fax: 314-747-9320,  
E-mail: mellis@dom.wustl.edu 
 
Nadine Tung, MD 
Beth Israel Deaconess Medical Center 
330 Brookline Avenue 
Boston, MA 02215 
Tel: 617-667-0982 
Fax: 617-975-5665 
E-mail: ntung@bidmc.harvard.edu 
 
 
Statistician: 
 
 
 
 
 
 
Hao Guo M.S. 
Department of Biostatistics and Computational Biology 
Dana-Farber Cancer Institute 
450 Brookline Ave. (CLS 11059) 
Boston, MA 02215 
Ph: 617-632-3626 
Fax: 617-632-5444 
Hao_Guo@dfci.harvard.edu 
 
 
Responsible Research Nurse:   
Margaret Haldoupis, RN 
  
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Ph: 617-632-3800 
Fax: 617-632-1930 
 
Study Coordinator: 
Rebecca Rees 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 
Ph: 617-632-6651 
Fax: 617-632-3550 
ArielleM_Brackett@DFCI.HARVARD.EDU 
 
Other Agent(s): Palbociblib- Pfizer   
                            Bazedoxifene- Pfizer 
 
 


 
 
 
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IND #:  126206 
IND Sponsor:  Rinath Jeselsohn, MD   
 
Protocol Type / Version # / Version Date:  
Revision / Version #9 / October 18, 2017 
 
 
 


 
 
 
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SCHEMA                                 
ER+ Metastatic Breast Cancer 
At least 1 prior endocrine therapy (adjuvant or metastatic) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent to clinical trial 
Baseline study tests: 
Retrieval of archival specimens of primary tumor or metastatic tissue 
when available 
--Required biopsy for patients with easily accessible disease 
--Required biopsy for patients with accessible disease 
--Plasma for cfDNA, whole blood, serum. 
Begin Palbociclib in combination with Bazedoxifene 
 
1st  stage N=17 patients 
Restage every 2 cycles 
(1 cycle=28 days) 
PD 
Off-study 
CR, PR, or SD 
Continue on  
protocol therapy 
--CBC with differential on D1 and D15 of Cycles 1-3 
and thereafter on Day 1 of each cycle. Chemistries on 
Day 1 of each cycle. 
--Optional  biopsy on Cycle 1 for patients with easily 
accessible disease. 
--Optional biopsy on Cycle 1 for patients with 
accessible disease. 
--Plasma for cfDNA on D1 of each cycle 
 
--Required  biopsy for patients with easily 
accessible disease and progressive disease. 
--Optional biopsy for patients with accessible 
disease. 
-- Plasma for cfDNA  
≥4 patients with clinical 
benefit at 24 weeks. 
<4 patients with clinical 
benefit at 24 weeks 
Discontinue 
accrual 
   2nd stage  
N= 20 
1st 6 patients safety 
run-in 
1 dose de-
escalation 
Continue 
accrual 
≤1 patient with a DLT 
>1 patient 
with a DLT 
≤1 patient 
with a DLT 


 
 
 
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TABLE OF CONTENTS 
 
SCHEMA .....................................................................................................................................................5 
1. 
OBJECTIVES ..................................................................................................................................8 
1.1 
Study Design ........................................................................................................................8 
1.2 
Primary Objectives ...............................................................................................................8 
1.3 
Secondary Objectives ...........................................................................................................8 
1.4 
Correlative Objectives .........................................................................................................8 
2. 
BACKGROUND .............................................................................................................................9 
2.1 
Study Disease(s)...................................................................................................................9 
2.2 
IND Agents ..........................................................................................................................9 
2.3 
Rationale ............................................................................................................................15 
2.4 
Correlative Studies Background ........................................................................................16 
3. 
PARTICIPANT SELECTION .......................................................................................................20 
3.1 
Eligibility Criteria ..............................................................................................................20 
3.2 
Exclusion Criteria ..............................................................................................................24 
3.3 
Inclusion of Women and Minorities ..................................................................................25 
4. 
REGISTRATION And recruitment PROCEDURES ....................................................................25 
4.1 
Recruitment Procedures .....................................................................................................25 
4.2 
General Guidelines for DF/HCC and DF/PCC Institutions ...............................................25 
4.3 
Registration Process for DF/HCC and DF/PCC Institutions .............................................25 
5. 
TREATMENT PLAN ....................................................................................................................26 
5.1 
Treatment Regimen ............................................................................................................27 
5.2 
Pre-Treatment Criteria .......................................................................................................27 
5.3 
Agent Administration .........................................................................................................28 
5.4 
General Concomitant Medication and Supportive Care Guidelines ..................................28 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .....................................................30 
5.6 
Duration of Follow Up .......................................................................................................30 
5.7 
Criteria for Removal from Study Follow-up .....................................................................30 
6. 
DOSING DELAYS/DOSE MODIFICATIONS............................................................................31 
6.1 
Toxicity Management ........................................................................................................31 
6.2 
Dose Modifications/Delays ................................................................................................31 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................................35 
7.1 
Adverse Events Lists..........................................................................................................36 
7.2 
Adverse Event Characteristics ...........................................................................................36 
7.3 
Expedited Adverse Event Reporting to DF/HCC ..............................................................37 
7.4 
Expedited Reporting to Pfizer ............................................................................................37 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ..................................38 
7.6 
Expedited Reporting to Hospital Risk Management .........................................................38 
7.7 
Routine Adverse Event Reporting .....................................................................................38 
8. 
PHARMACEUTICAL INFORMATION ......................................................................................38 


 
 
 
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8.1 
Palbociclib..........................................................................................................................38 
8.2 
Bazedoxifene......................................................................................................................41 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................................42 
9.1 
Research Tissue Specimen Collection ...............................................................................42 
9.2 
Blood Sample Collection ...................................................................................................43 
9.3 
Drug Adherence .................................................................................................................43 
10. 
STUDY CALENDAR ...................................................................................................................43 
11. 
MEASUREMENT OF EFFECT....................................................................................................46 
11.1 
Antitumor Effect – Solid Tumors ......................................................................................46 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .......................................................52 
12.1 
Data Reporting ...................................................................................................................52 
12.2 
Data Safety Monitoring ......................................................................................................53 
12.3 
Collaborative Agreements Language .................................................................................53 
13. 
STATISTICAL CONSIDERATIONS...........................................................................................53 
13.1 
Study Design/Endpoints.....................................................................................................53 
13.2 
Sample Size, Accrual Rate and Study Duration ................................................................55 
13.3 
Analysis of Primary Endpoints ..........................................................................................55 
13.4 
Analysis of Secondary Endpoints ......................................................................................55 
13.5 
Reporting and Exclusions ..................................................................................................56 
14. 
PUBLICATION PLAN .................................................................................................................57 
REFERENCES ..........................................................................................................................................58 
APPENDIX A  ECOG PERFORMANCE STATUS CRITERIA .............................................................61 
APPENDIX B  LIST OF DRUGS KNOWN TO PREDISPOSE TO TORSADE DE POINTES ............62 
APPENDIX C  CYP3A INDUCERS/INHIBITORS AND INFORMATION ON POSSIBLE DRUG 
INTERACTIONS ..........................................................................................................................63 
APPENDIX D  STUDY PARTICIPANT SELF-ADMINISTERED DRUG DIARY ..............................64 
APPENDIX E  RESEARCH SPECIMEN COLLECTION/SHIPPING GUIDELINES ...........................67 
APPENDIX F  INVESTIGATOR-INITIATED RESEARCH DRUG SUPPLY REQUEST ...................69 
APPENDIX G  PHARMACY RECOMMENDATIONS FOR DISPENSING PALBOCICLIB .............71 
APPENDIX H  REPORTABLE EVENT FAX COVER SHEET FOR REPORTING TO PFIZER ........72 
 
 
 


 
 
 
Page | 8  
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is a non-randomized, open-label, phase Ib/II study designed to evaluate the safety and efficacy of 
palbociclib, an oral selective CDK 4/6 inhibitor in combination with bazedoxifene, a third generation selective 
estrogen receptor modulator (SERM) in patients with metastatic hormone receptor positive breast cancer. 
Patients must have hormone receptor positive (HR+) disease and HER2 negative disease (defined as ER ≥10% 
or PR≥10%, and HER2- negative by IHC and/or FISH). Patients must have received at least 1 prior endocrine 
treatment regimen in the advanced setting or have relapsed less than 12 months from completion of adjuvant 
endocrine treatment. Patients will be re-staged every 2 cycles and will remain on study until there is evidence of 
progressive disease, unacceptable toxicity, or withdrawal of consent. A safety run-in will be performed after the 
accrual of the first 6 patients.  No more than 1 of 6 patients is to have a dose limiting toxicity before continuing 
accrual. If more than 1 patient has a dose limiting toxicity, an additional 6 patients will be accrued for a dose 
de-escalation safety run-in. If more than 1 of 6 patients has a dose limiting toxicity in the dose de-escalation 
safety run-in, accrual to the study will be discontinued. In the first stage of the two-stage design, 17 patients will 
be enrolled. If at 24 weeks there are at least 4 patients with clinical benefit accrual will continue to the second 
stage where up to 20 additional patients will be enrolled.  If at least 11 of these 37 patients have clinical benefit, 
the regimen will be considered worthy of further study.   
 
1.2 
Primary Objectives 
 
• To evaluate the clinical benefit rate (CR + PR + SD ≥ 24 weeks) of palbociclib and bazedoxifene in 
advanced HR+ /HER2- breast cancer. 
 
1.3 
Secondary Objectives 
 
• To determine the safety and toxicity profile  
• To determine the objective response rate in patients receiving palbociclib and bazedoxifene.  
• To determine the progression-free survival of patients receiving palbociclib and bazedoxifene. 
• To determine the overall survival of patients receiving palbociclib and bazedoxifene. 
• To assess the objective response, clinical benefit rate, progression free survival and overall survival for 
patients with ESR1 mutations. 
 
1.4 
Correlative Objectives 
 
The correlative studies proposed in this protocol are exploratory and hypothesis-generating. Promising 
hypotheses may be further explored and/or validated in future studies. 
 
• To explore whether high levels of cyclin D1or phosphorylated Rb are associated with objective response 
• Validate the mechanism of action of palbociclib and bazedoxifene by looking at phosphorylated  Rb 
levels, ER levels and ER target gene levels at cycle 1.   
• To explore if there is an association between specific genetic alterations and objective response or 
overall survival by performing Next Generation Sequencing (NGS) in archival metastatic tumor samples 
and /or prospectively collected metastatic samples. 
• Study mechanisms of resistance by studying expression levels of ER, Cyclin D1, phosphorylated Rb and 
the CDK inhibitors p21, p27 and p16, EGFR, and phosphorylated AKT and by performing NGS of 
tumors attained after the development of resistance.  
• To explore the sensitivity of plasma cell free DNA (cfDNA) and droplet digital PCR (ddPCR) to detect 


 
 
 
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mutations in metastatic breast cancer. 
• To analyze if changes in levels of mutations as determined by plasma cfDNA and ddPCR correlate with 
response or resistance to treatment. 
• Objective response, Clinical benefit rate, Progression free survival and Overall survival in patients with 
ESR1 mutations. 
 
In addition to the above studies, specimens will be collected and archived for future studies. 
• To collect primary and metastatic samples for future studies  
• To collect plasma at baseline and time of progression for future studies 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
The majority of breast cancer mortality is due to hormone receptor positive (HR+) disease [1]. Endocrine 
treatments are the mainstay therapy for ER+ breast cancer. These treatments include targeting the ER for 
inhibition using the antagonist tamoxifen, reducing ER activation by suppressing endogenous estrogen 
production by using aromatase inhibitors (AI) and more recently down regulating and enhancing ER 
degradation by selective ER degraders (SERDs). Despite effective endocrine treatments, de-novo and acquired 
endocrine resistance remains an important clinical challenge. This underscores the need for new therapeutic 
strategies to treat HR+ metastatic breast cancer.  
 
2.2 
IND Agents 
 
2.2.1 Palbociclib 
 
PD-0332991 (palbociclib), an orally active pyridopyrimidine, is a potent first-in-class, highly selective 
reversible inhibitor of CDK4 and CDK6 (IC50 = 11 nM; Ki = 2 nM) with a molecular weight of 447.53. Data 
from nonclinical studies indicate that palbociclib may have cytoreductive as well as cytostatic effects on tumor 
cells. The compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into 
the S phase, as demonstrated both in laboratory models and in early clinical trials. CDK4 and CDK6 control G1 
to S phase transit by binding to D-type cyclins [2-4].  The CDK4/6/Cyclin D1 complex phosphorylates the 
retinoblastoma susceptibility (RB1) gene product (Rb), releasing the E2F and DP transcription factors that drive 
expression of genes required for S-phase entry. CDK activity and G1 progression is negatively regulated by 
Cip-Kip ( P27,P21) and INK4 family, typified by p16 [5-9]. Overexpression of p16 in cells with normal Rb 
inhibits both CDK4-and CDK6- associated kinase activity and Rb phosphorylation, with subsequent cell cycle 
arrest [10, 11]. 
 
There is a strong link between the actions of estradiol and the G1-S phase transition, where the estradiol effector 
is the cyclin D1-CDK4/6-Rb complex [12]. Cyclin D1 is a direct transcriptional target of ER [13, 14] and 
microinjection of antibodies to cyclin D1 inhibits estrogen-induced S-phase entry. In addition, anti-estrogen-
induced growth arrest of ER+ breast cancer cells is accompanied by decreased cyclin D1 expression [15], while 
endocrine resistance is associated with persistent cyclin D1 expression and Rb phosphorylation [16]. Consistent 
with the notion that the main function of cyclin D1 is to activate CDK4/6, its oncogenic activity is dependent on 
CDK4/6-associated kinase activity [17] and CDK4/6 inhibitors are most effective in tumors with gene 
amplification and overexpression of cyclin D1 [18-20], which is common in ER+ breast cancer. Genetic 
aberrations leading to hyperactivation of cyclin D1-CDK4/6 is particularly common in ER+ breast cancer [21], 
consistent with its critical role in the tumorigenesis of this cancer subtype, making CDK4/6 inhibitors 
particularly attractive agents for ER+ breast cancer. 
 


 
 
 
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Palbociclib Preclinical Data 
 
Palbociclib preclinical data indicate that it may be expected to have direct effect on growth arrest as well as 
potential secondary cytoreductive activity. Single agent palbociclib has shown antiproliferative effects 
(selective G1 arrest) on Rb-positive cancer cells in vitro and in vivo [19] where palbociclib activity was 
associated with reduced Rb-phosphorylation and decreased expression of the cell proliferation marker Ki67. 
Palbociclib showed no activity in Rb-negative tumor cell xenografts, consistent with CDK4/6 inhibition as the 
sole mode of action [19]. 
 
Treatment of cultured tumor cells with palbociclib causes growth arrest that is accompanied by the inhibition of 
specific pRb phosphorylation by CDK4 or CDK6 on residues serine -780 and -795 of pRb. The IC50 values for 
reduction of pRb phosphorylation at serine -780 and -795 in MDA-MB-435 breast carcinoma cells were 0.066 
and 0.063 μM, respectively. The IC50 values for reduction of pRb phosphorylation are similar to the IC50 values 
of inhibition of thymidine incorporation across a range of cultured tumor and normal cells.  
 
Palbociclib was tested in vitro on molecularly characterized human breast cancer cell lines. Results from these 
experiments indicate that those cell lines that are more sensitive to palbociclib (IC50 < 150 nM) have low levels 
of CDKN2A (p16) and high levels of Rb1, while resistant cell lines show the opposite characteristics. In this 
study, ER+ breast cancer seems to be particularly appropriate for treatment with palbociclib; sensitive cell lines 
in this panel represent mostly the luminal ER+ subtype [29]. The combination of palbociclib with tamoxifen has 
been tested in vitro in ER+ breast cancer cell lines indicating a synergistic interaction  and provided a biologic 
rationale for evaluating the combination of palbociclib with anti-hormonal therapy in the clinic.  
 
In nonclinical studies, palbociclib and its active lactam metabolite, PF-05089326, demonstrated little or no 
inhibition of cytochrome P450 (CYP) 1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 enzyme 
activities and thus, showed low potential for PK DDI with drugs that are substrates for these CYPs. However, 
palbociclib and its metabolite, PF-05089326, caused time-dependent inhibition of CYP3A-mediated midazolam 
1’-hydroxylase and testosterone 6β-hydroxylase activities and, therefore, may have the potential for PK DDI 
with drugs for which CYP3A-mediated metabolism constitutes the primary mechanism of clearance. 
Palbociclib did not cause induction of CYP1A2, CYP2B6, CYP2C8, or CYP3A4 messenger ribonucleic acid 
expression and/or enzyme activity in vitro in human hepatocytes at concentrations exceeding 50-fold of the 
palbociclib unbound steady-state plasma Cmax determined at therapeutic doses in humans; thus, the potential for 
palbociclib to induce these enzymes is considered to be low at clinically relevant concentrations. The potential 
for palbociclib to inhibit the activities of selected uridine diphosphate glucuronosyltransferase (UGT) enzymes 
(UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) was also assessed, and the likelihood of DDI 
associated with inhibition of these Phase 2 enzymes at clinically relevant concentrations is considered low. 
 
Inhibition of efflux transporters (p-glycoprotein [P-gp] and breast cancer resistant protein [BCRP]), hepatic 
uptake transporters (organic anion-transporting polypeptide (OATP) 1B1  and OATP1B3), hepatic efflux 
transporter (bile salt export pump [BSEP]), and renal transporters (organic anion transporter [OAT] 1, OAT3, 
and organic cation transporter [OCT] 2) by palbociclib was assessed in vitro and was considered to be unlikely 
at clinically relevant palbociclib concentrations.  
 
In vitro, palbociclib is metabolized mainly by CYP3A and sulfotransferase 2A1 (SULT2A1) enzymes. Drugs 
that are known to induce or inhibit the activities of these enzymes may alter the clearance and systemic 
exposure of palbociclib. 
 
Palbociclib Pharmacokinetic (PK) Data 
 
To date, pharmacokinetic data have been collected in 8 clinical studies for a total of over 250 advanced cancer 


 
 
 
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patients and 30 healthy volunteers (A5481001, A5481002, A5481003, A5481004, A5481008, A5481009, 
A5481010, and A5481011). In the FIP trial (A5481001) the exposure increased in a dose proportional manner 
over the dose range of 25 to 225 mg QD following palbociclib administration on Days 1 and 8 of Cycle 1, 
although some variability (low to moderate) around these doses was observed particularly at the 150 mg QD 
dose level. Following repeated daily dosing to steady state, palbociclib was absorbed with a median Tmax of ~4 
hours. The mean palbociclib Vz/F was 2583 L, which is significantly greater than total body water (42 L), 
indicating that palbociclib extensively penetrates into peripheral tissues. Palbociclib was eliminated slowly; the 
mean elimination half-life (t1⁄2) was 28.8 hours  and the mean CL/F was 63.1 L/hour. Palbociclib accumulated 
following repeated dosing with a median Rac of 2.4, which is consistent with the terminal half-life. 
 
The effect of food on the bioavailability of palbociclib when administered as the commercial free base capsule, 
was investigated in Study A5481021. The administration of the free base formulation of palbociclib with food 
(including a high fat or a low fat meal given together with palbociclib, or moderate fat meals given 1 hour 
before and 2 hours after palbociclib) resulted in more uniform drug absorption and significantly reduced the 
intersubject variability in drug exposure when compared to the administration of free base formulation of 
palbociclib in a fasted state. The relative bioavailability of the commercial free base capsule administered with 
food and the isethionate capsule administered under overnight and minimal fasting conditions was investigated 
in Study A5481036. The two fasting conditions for administration of isethionate capsules represent the 2 
extreme scenarios for compliant palbociclib dosing with regard to food intake in the pivotal Phase 1/2 efficacy 
trial, Study A5481003, in which patients were instructed to fast from 1 hour before until 2 hours after 
palbociclib dosing. The administration of palbociclib free base capsule formulation with food was found to be 
bioequivalent to palbociclib isethionate capsule formulation given under both the overnight and minimal fasting 
conditions. As a result of these findings, it is recommended that free base formulations of palbociclib be 
administered with food. 
 
Pharmacokinetic data are available from an itraconazole DDI study where the effect of multiple dosing of a 
potent CYP3A4 inhibitor, itraconazole (200 mg QD), on the single-dose PK of palbociclib (125 mg) was 
evaluated in 12 healthy fasted subjects (Study A5481016). Median palbociclib plasma concentrations were 
higher in the presence of itraconazole than those in the absence of itraconazole. Palbociclib mean plasma AUC 
from time 0 to infinity (AUCinf ) and Cmax values increased approximately 87% and 34%, respectively, when 
administered in combination with itraconazole compared to when administered alone. Therefore, concomitant 
administration of agents known to be strong inhibitors of CYP3A isoenzymes (such as ketoconazole, 
miconazole, itraconazole, posaconazole, clarithromycin, erythromycin, telithromycin, nefazodone, diltiazem, 
verapamil, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and 
grapefruit juice) should be avoided. 
 
Pharmacokinetic data are available from a rifampin DDI study where the effect of multiple dosing of a potent 
CYP3A4 inducer, rifampin (600 mg QD), on the single-dose PK of palbociclib (125 mg) was evaluated in 15 
healthy fasted subjects (Study A5481017). Median palbociclib plasma concentrations were substantially lower 
in the presence of rifampin than those in the absence of rifampin. Palbociclib mean plasma AUC from time 0 to 
infinity (AUCinf ) and Cmax values decreased approximately 85% and 70%, respectively, when administered in 
combination with rifampin compared to when administered alone. Therefore, co-administration of palbociclib 
with strong CYP3A inducers (such as phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, 
clevidipine, and St. John’s Wort) should be avoided. 
 
Palbociclib and PF-05089326 caused time-dependent inhibition of CYP3A in in vitro assays. Pharmacokinetic 
data are available from a midazolam DDI study where the effect of multiple dosing of palbociclib (125 mg QD) 
on the single-dose PK of a sensitive CYP3A4/5 probe substrate, oral midazolam (2 mg), was evaluated in 26 
healthy women of non-childbearing potential (Study A5481012). When midazolam was administered with 
palbociclib 125 mg QD at steady-state, the mean midazolam plasma Cmax and AUCinf values increased 


 
 
 
Page | 12  
approximately 38% and 61%, respectively, as compared with those determined after administration of 
midazolam alone. These results indicate that palbociclib is a weak time-dependent inhibitor of CYP3A. 
 
Palbociclib Dose Rationale 
 
Palbociclib has been tested in a Phase 1 dose escalation Study (A5481001) in 74 patients with advanced cancer. 
Two dosing schedules were evaluated: Schedule 3/1 (3 weeks on treatment/1 week off treatment) and Schedule 
2/1 (2 weeks on treatment/1 week off treatment). All dose limiting toxicities (DLTs) observed in this study were 
related to myelosuppression and mainly consisted of Grade 3 neutropenia lasting more than 7 days after the end 
of the treatment cycle. However, neutropenia was reversible and non-cumulative. The most common non-
hematological adverse events included fatigue, anemia, diarrhea, constipation, vomiting and dyspnea, all with 
mild to moderate severity. A greater proportion of patients on the 2/1 schedule had treatment-related TEAEs 
during and after Cycle 1 than patients on the 3/1 schedule although the proportion of patients with treatment-
related neutropenia was similar with respect to the 2 dosing schedules, both during and after Cycle 1. One 
partial response (PR) was reported in a patient with testicular cancer. A total of 13/37 patients treated with 
Schedule 3/1 evaluable for efficacy experienced stable disease (SD), including 6 patients with SD lasting 40 
weeks or longer. One of these patients was a woman with ER+ breast cancer who had previously received 7 
lines of treatment for her disease. This patient remained on treatment for 80 weeks (7 cycles at 50 mg/d and 13 
cycles at 75 mg/d) and eventually discontinued treatment due to disease progression. Based on the relatively 
improved safety profile of Schedule 3/1, and the efficacy results from this study, the Schedule 3/1 has been 
selected for further clinical development and the RP2D for this schedule was determined to be 125 mg/day. This 
schedule and associated RP2D was further explored in combination with letrozole in the Phase I/II study in 
patients with advanced breast cancer described below. 
 
Palbociclib Clinical Data 
 
A phase II study with single agent palbociclib in 36 women with advanced breast cancer was reported at the 
American Society of Clinical Oncology (ASCO) 2013 from 28 women who have completed cycle 1 [30]. 
Palbociclib is given at 125 mg orally, days 1- 21 of a 28-day cycle. Of the 28 women, 18 (64%) women are 
HR+/HER2-, 2 (7%) are HR+/HER2+ and 8 (29%) HR-/HER2-negative. 90% had prior chemotherapy for 
metastatic disease (median 3 lines); 78% had prior hormonal therapy (median 2 lines). Grade 3/4 toxicities were 
limited to transient neutropenia (n=14; 50%) and thrombocytopenia (n=6; 21%). One episode of febrile 
neutropenia occurred in a patient with six previous chemotherapy regimens. All other toxicities were grade 1/2. 
Treatment was interrupted in 7 (25%) and dose reduced in 13 (46%) patients for cytopenias; 27/28 patients 
discontinued study for disease progression. (PR + SD >6 months) was as follows: 4 patients (23%) in 
HR+/HER2-negative (n=18), 1 (50%) in HR+/HER2+ (n=2), 1 (13%) in HR-negative/HER2-negative (n=8). In 
conclusion, therapy with palbociclib alone is well-tolerated, and demonstrates clinical benefit in patients with 
all subtypes of breast cancer and despite progression on prior hormonal- and chemotherapy. Translational 
studies examining molecular predictors of response are in progress. 
 
A randomized, multicenter active-controlled Phase I/II Study (A5481003) was designed to assess the efficacy, 
safety and PK of letrozole 2.5 mg QD in combination with palbociclib 125 mg QD (schedule 3/1) versus single 
agent letrozole 2.5 mg QD for the first-line treatment of ER+/ HER2-negative advanced breast cancer in 
postmenopausal women. Letrozole was selected as the active control based on its worldwide approval and use 
as standard of care for the first-line hormonal treatment of postmenopausal women with ER+ advanced breast 
cancer. 
Study A5481003 included a limited Phase I portion, aimed at confirming the safety and tolerability of the 
combination and excluding a PK interaction with the combination, and a randomized Phase II portion aimed at 
evaluating the efficacy and safety of letrozole in combination with palbociclib when compared to letrozole 
alone in the first-line treatment of postmenopausal patients with ER+/HER2-negative advanced breast cancer. 


 
 
 
Page | 13  
The Phase II portion, also called PALOMA-1, consisted of 2 parts. In Part 1, patient selection was based only 
on ER/HER2 status. In Part 2, patients were prospectively selected also taking into account tumor CCND1 
amplification and/or p16 loss. A total of 177 patients were enrolled in the study. Twelve (12) were enrolled in 
the Phase 1 portion and 165 (66 and 99 in Part 1 and 2, respectively) were enrolled in the Phase 2 portion. 
Results from the Phase 1 portion indicated no PK interaction between palbociclib and letrozole. The RP2D was 
determined to be 125 mg QD on Schedule 3/1 (3 weeks continuous treatment followed by 1week off treatment) 
in combination with letrozole 2.5 mg QD continuously. PRs were reported for 3 (33%) out of 9 patients with 
measurable disease (3 had bone-only disease). Another 5 patients (42%) had stable disease for ≥ 6 months and 
the clinical benefit rate (PR + SD ≥ 6 months) was 67%. Eight (8) patients discontinued from the study due to 
disease progression, including 2 patients with clinical progression, 1 patient withdrew consent, and 3 patients 
are still ongoing. 
 
Two interim analyses for the Phase 2 portion of the study have been conducted. The results of the interim 
analyses showed consistent trend of clinically meaningful improvements in PFS (primary endpoint). In the first 
interim analysis (Part 1; N=66), the median PFS for the palbociclib plus letrozole arm was 18.2 months versus 
5.7 months for the letrozole alone arm (HR=0.35; 95% CI: 0.17, 0.72; p=0.006). The second interim analysis 
(N=165) continued to demonstrate a statistically significant improvement in PFS (26.1 vs. 7.5 months, 
respectively; HR=0.37; 95% CI: 0.21, 0.63; p <0.001) [22]. More recently, the final analysis demonstrated a 
statistically significant improvement in PFS for the palbociclib plus letrozole arm (20.2 months) versus the 
letrozole arm (10.2 months) with hazard ratio (HR=0.488; 95% CI: 0.319, 0.748, p=0.0004). These results 
indicate that the combination of palbociclib with letrozole is well tolerated with a safety profile similar to that 
seen with either palbociclib or letrozole when administered alone. The most frequently reported treatment-
related adverse events included neutropenia, leukopenia, anemia, and fatigue. There were no cases of febrile 
neutropenia reported to date in this study. Overall, 8 patients in the combination arm were discontinued from 
the study treatment due to an adverse event, of which 5 were considered treatment-related (grade 3 neutropenia 
[n=4] and ischemic colitis) and 1 patient from the letrozole alone arm. Additionally, the combination 
demonstrated antitumor activity, which was consistent with the sensitivity of ER+ breast cancer observed in the 
preclinical models.  
 
2.2.2 Bazedoxifene 
 
Bazedoxifene is an orally available indole-based selective estrogen receptor modulator (SERM) with two 
phenyl rings that serve as the core-binding unit. Its structural characteristics differ from those of tamoxifen and 
raloxifene. Bazedoxifene (20 mg) is approved in the European Union for the treatment of post-menopausal 
osteoporosis in women at increased risk of fracture. Bazedoxifene has not been approved in the United States. 
Bazedoxifene emerged from in-vitro screens that selected for compounds that bound to ER and competitively 
displaced 17β-estradiol, inhibited estrogen action in estrogen models and did not manifest ERα agonist activity 
in contexts where tamoxifen functions as an agonist, as in the endometrium. 
 
Based on in-vitro studies, bazedoxifene does not stimulate MCF7 breast cancer cell proliferation and suppresses 
breast cancer cell proliferation induced by 17β-estradiol in a dose dependent manner [23]. In animal studies, 
treatment with bazedoxifene preserved bone mass and bone strength and decreased levels of bone turnover 
markers. In immature rats, bazedoxifene protected against estrogen-stimulated increases in uterine wet weight. 
In mice it was a more effective antagonist against conjugated estrogen induced stimulation of the mammary 
gland compared to other SERMs [24] 
 
Bazedoxifene Preclinical Data 
 
Preclinical studies show that bazedoxifene inhibits estrogen induced cell growth in ER+ breast cancer cell lines 
with an IC50 of 0.19nM. This inhibition is due to antagonistic effect of bazedoxifine on ER, as the growth 


 
 
 
Page | 14  
effect is lost with ER knock-down by siER. In addition, bazedoxifene also inhibits the ligand independent cell 
growth of clonally derived long-term estrogen deprived cells, a cellular model of aromatase inhibitor resistance. 
Fulvestrant also has an inhibitory effect on these resistant cells but requires a higher concentration. 
Additionally, bazedoxifene induces G1-phase cell cycle block by directly reducing Cyclin D1 levels [25].  
Breast cancer xenograft studies showed that bazedoxifene inhibits tumor growth and reduced tumor doubling 
time. Similarly, in a tamoxifen resistant breast cancer xenograft model in which growth is stimulated by 
tamoxifen, bazedoxifene treatment reversed the tamoxifen stimulation of these tumors and led to tumor 
regression [26]. 
 
Both in-vitro and in-vivo studies show that bazedoxifene has SERD activity, which is proteasome dependent. 
Furthermore, in the presence of bazedoxifene, ER mRNA levels do not increase in response to increased ER 
degradation, resulting in sustained knock-down of ER over time in the absence of a feedback mechanism to 
restore receptor levels [26]. 
 
Bazedoxifene Pharmacokinetic (PK) data 
 
Pharmacokinetic studies were conducted in healthy post-menopausal women. In one study, women received 
multiple doses of 5, 20 and 40 mg bazedoxifene daily in a randomized crossover fashion for 14 days. The 
maximum concentration (Cmax) was dose dependent and was reached within 1-2 hours. The half-life of 
bazedoxifene was 28 hours. Bazedoxifene exhibited linear pharmacokinetics. Plasma concentrations were 
approximately double at steady state, which was reached by day 7. Protein binding was greater than 99%. 
Results from a metabolic disposition study showed that the major route of excretion was feces (85%), with less 
than 1% excreted in the urine. The major metabolic pathway was glucuronidation, with little or no cytochrome 
P450 metabolism. 
 
Bazedoxifene Dose Rationale 
 
Bazedoxifene has been tested in a 2 part, 6 month, double blind, randomized, active and placebo controlled study 
that included 497 healthy post-menopausal women. Conjugated estrogen (0.625 mg )/ medroxy-progesterone 
actetate (2.5) was the active control. Bazedoxifene doses in the first part included daily 2.5 mg, 5mg, 10mg and 
20mg and in the second part daily 20mg (n=60), 30mg (n=60) and 40mg (n=60) [27]. Endometrial thickness was 
monitored closely and doses 2.5 -20mg/ day resulted in no significant endometrial thickness changes compared to 
placebo. The 30 and 40mg/day doses were associated with a decrease in endometrial thickness, which was 
inversely related to dose. None of the endometrial biopsy specimens demonstrated endometrial hyperplasia. The 
most commonly reported adverse events were: abdominal pain, headache, breast pain and flu syndrome. One 
possible related serious adverse event was an episode of supraventricular tachycardia after a concomitant use of a 
salbutamol inhaler. 
 
A double-blind, placebo-controlled, ascending multiple-dose safety and tolerability study of bazedoxifene was 
conducted including 107 healthy postmenopausal women (information from Pfizer). Fifteen (15) subjects (12 to 
receive Bazedoxifene and 3 to receive placebo) participated in each of the 7 dose groups. The 7 oral doses of 
Bazedoxifene were 1, 2.5, 5, 10, 20, 40, and 80 mg, given once daily for 30 consecutive days. One (1) or more 
adverse events were reported by 78 (73%) subjects; 10 (77%) who took Bazedoxifene 1 mg, 8 (62%) who took 
Bazedoxifene 2.5 mg, 7 (58%) who took Bazedoxifene 5 mg, 9 (75%) who took Bazedoxifene 10 mg, 9 (75%) 
who took Bazedoxifene 20 mg, 10 (83%) who took Bazedoxifene 40 mg, 8 (67%) who took Bazedoxifene 80 
mg, and 17 (81%) who took placebo. The majority of adverse events (82%) were reported as mild and 18% 
were reported as moderate. There were no severe adverse. Of the 78 subjects who reported adverse events, 43 
(55%) reported adverse events that were considered as possibly, probably, or definitely drug-related by the 
investigator, and 35 (45%) that were considered as not drug-related. The most frequently reported adverse 
events were: headache reported by 19 subjects (18%), constipation reported by 13 (12%) subjects, accidental 


 
 
 
Page | 15  
injury reported by 10 (9%) subjects, and dizziness, pharyngitis, and nausea, each reported by 7 (7%) subjects. 
No overall differences between treatment groups and no dose-related differences in the frequency were 
observed. 
 A 2-year phase III, double blind, randomized study was performed to study the efficacy of bazedoxifene in the 
prevention of osteoporosis. In this study bazedoxifene was found to significantly prevent bone loss. A total of 
1583 healthy post-menopausal women with osteoporosis risk were randomized to receive daily bazedoxifene 10 
(n=321), 20 (n=322) or 40mg (n=319), raloxifene 60mg or placebo. All doses of bazedoxifene were generally well 
tolerated and exhibited a safety profile generally similar to that of placebo. The most common adverse events in all 
treatment arms were headache, infection, arthralgia, pain, hot flashes and back pain. Hot flashes were more 
common in all doses of bazedoxifene (ranging from 19.6-24.1%) compared to placebo (14.2%), but similar to 
raloxifene. Four deaths were reported during the study and two deaths were reported after withdrawal or 
completion of the study. Five of the deaths were not considered related to the administered treatment. One death in 
the bazedoxifene 40mg arm, a subject experienced a pulmonary embolism during a prolonged air flight 30 days 
after study completion, was considered by the investigator to be possibly related to treatment. There were no cases 
of endometrial hyperplasia or endometrial cancer in the bazedoxifene groups. There were significant increases in 
triglyceride levels in all bazedoxifene treated arms, but the number of subjects that developed hypertriglyceridemia 
was low (0.3-1.6%) [28]. 
 
A 3-year randomized phase III, double blind, randomized study was conducted in women with osteoporosis to 
assess the efficacy of bazedoxifene in reducing new vertebral fracture risk. A total of 7492 women were 
randomized to daily bazedoxifene 20mg (n=1886) or 40mg (n=1872), raloxifene 60mg or placebo. Bazedoxifene 
was shown to reduce the risk of vertebral fractures. Both doses of bazedoxifene were well tolerated. The incidence 
of adverse events, serious adverse events, and deaths were generally similar to that in the placebo group. The 
incidence of venous thromboembolic events (deep venous thrombosis/ pulmonary embolism) was higher in the 
treatment arms compared with the placebo arm (bazedoxifene 20 mg, 0.7%; bazedoxifene 40mg, 0.6%, raloxifene 
60mg 0.5% ; placebo 0.3%). The frequency of the development of breast cancer was lower in the bazedoxifene 
treatment arms relative to the raloxifene and placebo arms [29].  
 
The 40mg dose of bazedoxifene was chosen for this study given the extensive data of the safety of this dose in 
over 2000 patients, as described in the studies above, and the pre-clinical evidence of improved ER degradation 
and antagonistic activity with increasing doses of bazedoxifene (figure 1). Furthermore, several recent clinical 
studies have shown, that in metastatic disease, improved ER inhibition by increasing the dose of fulvestrant or 
combining fulvestrant with an aromatase inhibitor can result in improved clinical outcomes [30, 31]. Taken 
together, these studies suggest that a higher dose of bazedoxifene could have increased efficacy without added 
toxicity.  
  
2.3 
Rationale 
 
Combination of bazedoxifene with palbociclib: The combination of palbociclib and letrozole is a very 
promising regimen for the treatment of metastatic HR+ breast cancer. However, many patients with ER+ breast 
cancer receive an aromatase inhibitor as part of adjuvant hormonal therapy or as a single agent as first line 
treatment in the metastatic setting. A combination of palbociclib with an endocrine treatment of a different class 
is lacking and may be superior. 
 
Fulvestrant is an endocrine treatment that is a SERD and has a different mechanism of action compared to 
aromatase inhibitors. Fulvestrant is an approved drug for the treatment of aromatase inhibitor refractory disease 
and the combination of palbociclib with fulvestrant is a potential regimen. However, the response rate to 
fulvestrant in the setting of refractory disease is approximately 10%, similar to exemestane, as a second line 
steroidal aromatase inhibitor. The low efficacy of fulvestrant is likely not to due to its mechanism of action but 


 
 
 
Page | 16  
rather, the pharmacokinetic properties of fulvestrant, which is administered by intramuscular injection, is the 
limiting factor. Indeed, despite the use of higher loading doses, drug concentrations measured in the vicinity of 
the tumor were found to be insufficient to saturate ER [32]. In addition, positron emission tomography studies 
confirmed poor delivery of fulvestrant to the tumor. Higher doses of fulvestrant were shown to be associated 
with improved progression free survival and the 500mg dose of fulvestrant is now the standard of care [31]. 
Despite this improvement in the delivery of fulvestrant, it is likely, that the full therapeutic potential of SERD 
treatment has not been revealed with this drug.  
 
Bazedoxifene is an orally bioavailable SERM with SERD activity [33,34]. In-vitro and in-vivo studies show that 
bazedoxifene inhibits cellular proliferation and tumor growth similarly to fulvestrant. The bioavailability of 
bazedoxifene is likely pertinent to evaluate the full potential of a SERD in the treatment of refractory disease. In 
addition, bazedoxefine was shown to directly inhibit cyclin D1 and therefore bazedoxifene may potentiate the 
activity of palbociclib [34].  
 
We confirmed that bazedoxifene functions both as an ER antagonist and ER degrader. As shown below, we 
detected similar ER degradation levels when bazedoxifene was compared to fulvestrant. In contrast, when we 
looked at the inhibition of ER activity by using MCF7 cell stably infected with an ERE-luciferace promoter-
reporter construct, bazedoxifene displayed improved ER inhibition compared to fulvestrant (fig.1). In addition, 
our preliminary data in three different ER+ breast cancer cell lines show that single agent fulvestrant and 
bazedoxifene alone inhibit cell growth comparably. However, the combination of palbociclib with either 
fulvestrant or bazedoxifene inhibits cell growth in a synergistic manner, with the latter combination being 
significantly superior. We also tested the growth effects of the different treatments in long-term estrogen 
deprived (LTED) cell lines. In this cell line that models resistance to aromatase inhibitors, we saw that the 
combination of palbociclib with bazedoxifene also had synergistic activity. 
 
2.4 
Correlative Studies Background 
 
The correlative studies proposed in this protocol are exploratory and hypothesis-generating. Promising 
hypotheses may be further explored and/or validated in future studies. 
 
• To explore whether high levels of cyclin D1, Rb and/or phosphorylated Rb or low levels of p16, p27 are 
associated with objective response 
• To explore whether patients harboring a ESR1 mutation respond to the combination of palbociclib with 
bazedoxifene. 
• To explore if there is an association between genetic alterations most frequently found in hormone 
receptor positive breast cancer and objective response or overall survival by performing Next 
Generation Sequencing (NGS) in archival metastatic tumor samples and/or prospectively collected 
metastatic samples. 
• Study mechanisms of resistance by studying expression levels of ER, Cyclin D1, phosphorylated Rb and 
the Cdk inhibitors p21, p27 and p16, EGFR, and phosphorylated AKT as well as targeted NGS of 
tumors attained after the development of resistance.  
• To explore the sensitivity of plasma cell free DNA (cfDNA) and droplet digital PCR (ddPCR) to detect 
mutations in metastatic breast cancer. 
• To analyze if changes in levels of mutations as determined by plasma cfDNA and ddPCR correlate with 
response or resistance to treatment. 
 
 
 
 
 


 
 
 
Page | 17  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fig. 1:  Bazedoxifene activity compared to fulvestrant: Above: ER levels in MCF7 cells treated with 
increasing doses of bazedoxifene or fulvestrant (nM). 
Below: dose response curve of luciferase activity in MCF7 cells with stable expression of ERE-luciferase. 
Bazedoxifene IC50=0.12 nM, fulvestrant IC50=0.76nM. 
 
 
ER
Veh. 0.1 
1 
10 
100 
Fulv 
Baze 
Beta Actin 
0.1 
1 
10 
100 


 
 
 
Page | 18  
 
 
 
 
 
 
 
 
2.4.1 Cyclin D1,Rb, phosphorylated Rb p16 and p27 levels in archival, metastatic and time of progression 
samples 
 
Cyclin D1 level was tested in the phase II study PALOMA-1 and was not found to correlate with benefit from 
palbociclib. Therefore we will test additional proteins that are key proteins related to the CDK4/6-cyclinD1 
complex and might predict response to treatment. These proteins will be studied by immunohistochemistry 
(IHC) in archival tissue samples from the primary tumors and metastatic samples in order to test if the 
expression levels of these proteins are concordant and if both tissue sources can be utilized for the evaluation of 
these biomarkers. 
 
2.4.2 ESR1 Mutations 
 
We and other groups recently identified ESR1 mutations in approximately 15% of patients with metastatic ER+ 
breast cancer. In all studies, the ESR1 mutations are located in a hot spot in the ligand-binding domain [5-9]. In 
our study, ESR1 mutations were not detected in primary ER+ breast cancers and all patients harboring a 
mutation received at least one line of hormonal therapy. Additionally, we found a correlation between the 
mutation frequency and number of treatment lines in the metastatic setting; patients who received at least 3 lines 
of treatment in the metastatic setting had a 20% mutation frequency. Our pre-clinical data in ER+ breast cancer 
0
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Fig. 2: Cell growth curves: cell count analysis on days 1,3 and 5 of treatment in MCF7, 
ZR75 and T47D cells. LTED=long term estrogen deprived, Bz=bazedoxifene, Fv=fulvestrant,  
Pb=palbociclib, VEH=vehicle. Doses are in nM. 


 
 
 
Page | 19  
cell lines show that these mutations confer constitutive activity and relative resistance to tamoxifen and 
fulvestrant. Taken together, these results suggest the clonal selection of ESR1 mutations that render endocrine 
resistance in metastatic ER+ breast cancer.  
 
We hypothesize that the combination of bazedoxifene and palbociclib may be effective in overcoming treatment 
resistance mediated by the ESR1 mutations. This hypothesis stems from pre-clinical data suggesting that SERDs 
can inhibit tumor growth driven by ESR1, but higher doses are required. Given the oral bioavailability of 
bazedoxifene, this might be achieved with this agent. In addition, since cyclin D1 is one of the key proteins 
regulated by the ER and downstream to the mutation, it is an attractive target for overcoming resistance 
mediated ESR1 mutations. As shown in Figure 3, employing MCF7 cells lines with doxycycline induced ESR1 
mutations, we confirmed that the mutations confer relative resistance to tamoxifen and fulvestrant. In contrast, 
ER mutant cells remain sensitive to bazedoxifene, further supporting the rationale of this study.  
 
 
 
 
 
 
 
 
2.4.3 Whole exome next generation Sequencing 
 
The major advances in genomic sequencing capacity have enabled the completion of several large whole exome 
sequencing studies of primary breast cancer. In the TCGA study, luminal breast cancers were found to harbor 
the most significantly mutated genes, which could explain the high molecular and clinical heterogeneity of this 
breast cancer subtype. The most commonly altered genes in primary luminal-type breast cancers include; 
PIK3CA, TP53, MAP3K1, MAP2K4, GATA3, MLL3, CDH1, PTEN, NCOR1, FOXA1, ERBB2. The functional 
roles of these mutations in the development and progression of metastatic ER+ breast cancer have not been 
elucidated yet and whole exome sequencing studies of metastatic breast cancer are limited. Therefore, in this 
study we will perform whole exome sequencing of archival primary and metastatic samples as well as 
prospectively collected metastatic samples, in order to study the associations between mutations and response to 
Fig 3: Improved growth inhibition of ER mutants by bazedoxifene: Dose response curves 
and IC50 levels for cell growth in MCF7 cell with doxycycline inducible Y537S ESR1 mutation 
at day 5 of treatment.  DOX= doxycycline .  


 
 
 
Page | 20  
treatment. In addition, we and other groups detected ESR1 mutations in metastatic ER+ breast cancers of 
patients who developed endocrine resistance. In this study we will also study the ESR1 mutations in the tissue 
specimens to test if there is an association between these mutations and response.  As part of this study, we will 
analyze germline DNA from blood samples in order to confirm that the mutations detected in the tumor 
specimens are somatic mutations. 
 
2.4.4 Study mechanisms of resistance to palbociclib and bazedoxifene 
 
Metastatic tissue samples from patients who developed progressive disease will also be biopsied. These samples 
with be analyzed by IHC and whole exome NGS to study changes in protein expression and genomic alterations 
that are associated with the development of resistance to treatment. 
 
2.4.5 Cell-free DNA 
 
Tumor genotyping using cell-free plasma DNA (cfDNA) has the potential to enable non-invasive assessment of 
genetic alterations that are predictive of either response or resistance to a given treatment. Recently, the Janne 
lab has published the use of ddPCR of cfDNA to detect and quantify mutations in advanced lung cancer and 
melanoma [33]. Serial plasma genotyping of the lung cancer EGFR mutant in patients treated with erlotinib 
demonstrated pre-treatment detection of EGFR mutations, complete plasma response in most cases and 
increasing levels of mutations that confer resistance prior to the development of objective progression. 
 
In this study, plasma will be collected prior to treatment and with each cycle. cfDNA will be extracted and 
PIK3CA, ESR1, TP53, GATA3,NCOR1 and ERBB2 mutations will be assessed. Serial plasma samples will 
allow us to follow correlations between mutational changes as detected in cfDNA and response to treatment. 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Participants must have histologically confirmed invasive breast cancer that is metastatic or unresectable 
locally advanced. Histological documentation of metastatic/recurrent breast cancer is not required if 
there is unequivocal evidence for recurrence of the breast cancer. 
 
3.1.2 Estrogen and/or progesterone receptor positive breast cancer (>10% staining), as determined by 
pathology from either primary or metastatic site(s). Central confirmation is not required. 
 
3.1.3 HER2 negative, defined as 0-1+ by immunohistochemistry or FISH-negative (HER2 copy number <6 
and HER2/CEP17 ratio < 2.0). Central confirmation is not required. 
 
3.1.4 Postmenopausal women are eligible. Postmenopausal is defined as any of the following: 
• Age ≥ 60 years  
 
• Age <60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, 
toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local 
normal range. 
•  Premenopausal women who have been on a GnRH agonist for at least 3 consecutive months prior 
to study entry are eligible. Women in this group MUST remain on the GnRH agonist for the 
duration of protocol treatment.  


 
 
 
Page | 21  
• Status-post bilateral oophorectomy-After adequate healing post surgery. 
 
3.1.5  
Women age > 18 years of age. Men are excluded 
  Because no dosing or adverse event data are currently available on the use of palbociclib and 
bazedoxifene in participants <18 years of age, children are excluded from this study. In addition, breast 
cancer is exceedingly rare in individuals under 18 years of age. 
 
3.1.6 Participants must have measurable disease by RECIST 1.1. See section 11 for the definition of 
measurable disease.  
 
3.1.7 Bone only disease if there are lytic lesions is also allowed and treatment response will be evaluated 
based on the MD Anderson criteria. See section 11. 
 
3.1.8 Endocrine resistant breast cancer, defined as either: 
• Relapsed while on adjuvant endocrine therapy or within 1 year of completion of adjuvant 
endocrine therapy 
 
     -or- 
• Progression through at least one line of endocrine therapy for metastatic or locally advanced breast 
cancer. There is no limit on the number of prior endocrine therapies received. 
 
3.1.9 Patients may have received up to one prior line of chemotherapy for metastatic or unresectable locally 
advanced breast cancer. 
 
3.1.10 Patients may have initiated bisphosphonate therapy prior to start of protocol therapy.   Bisphosphonate 
therapy may continue during protocol treatment. Such patients will have bone lesions considered 
evaluable for progression 
 
3.1.11 Patients must be at least 2 weeks from prior chemotherapy, including biologics or targeted therapy (i.e. 
everolimus), or radiotherapy, or any investigational drug product, with adequate recovery of toxicity to 
baseline, or grade  <1, with the exception of alopecia and hot flashes. There is no washout period for 
prior endocrine therapy. 
 
3.1.12 ECOG Performance Status 0-1 (Appendix A) 
 
3.1.13 Life expectancy of greater than 3 months 
 
3.1.14 Willingness to undergo research biopsy under the following circumstances: 
 
• Patients with “easily accessible disease” 
 
- 
Patients with skin or chest wall disease amenable to a punch biopsy under local anesthesia are 
required to undergo a baseline biopsy and a biopsy at the time of disease progression as part of 
this protocol.  
- 
Patients with a breast mass or axillary lymph node amenable to an image-guided core biopsy 
are also required to undergo a baseline biopsy and a biopsy at the time of disease progression 
as part of this protocol. 
- 
Patients with malignant ascites fluid or a malignant pleural effusion of sufficient volume to be 
amenable to tap (either in-office or image-guided) are also required to undergo a baseline tap 
and a tap at the time of disease progression as part of this protocol. 


 
 
 
Page | 22  
- 
Patients who undergo a research biopsy procedure for the purpose of this protocol, and in 
whom inadequate tissue is obtained, are still eligible and are not required to undergo a repeat 
biopsy in order to enter the study. 
- 
Patients will be approached during cycle 1 about providing an optional tissue sample at that 
time; however, this biopsy will be optional. 
 
• Patients with “accessible disease” 
 
- 
Patients with sites felt to be accessible to an image-guided or incisional biopsy in the opinion 
of the patient’s treating oncologist and physician performing the procedure, and not meeting 
the criteria for “easily accessible disease” as described in Section 3.1.14.1, are required to 
undergo a baseline biopsy as part of this protocol. Such sites may include, but are not limited 
to: liver, lymph nodes, soft tissue, lung, chest wall, and bone. Cycle 1 biopsy and biopsy at 
time of disease progression are optional.  
- 
Biopsies may be done with local anesthesia or intravenous conscious sedation, according to 
standard institutional guidelines.  
- 
If a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is 
necessary for clinical reasons (i.e. is clinically indicated), and excess tissue that would 
otherwise have been discarded is then used for research purposes. If a biopsy requires general 
anesthesia, then a biopsy of that site for research purposes only, without a coexisting clinical 
indication is not allowed on this protocol. 
- 
Patients who undergo a research biopsy procedure for the purpose of this protocol, and in 
whom inadequate tissue is obtained, are still eligible and are not required to undergo a repeat 
biopsy in order to enter the study. 
- 
Some patients may have had a clinically indicated biopsy upon recent disease progression. No 
additional pre-treatment biopsy is required if that specimen can be used for the correlative 
studies described in this protocol. 
- 
Patients will be approached at the time of progression about providing an optional tissue 
sample at that time; however, the time of progression biopsy will be optional. 
 
• Other patients 
 
 
Patients who do not have biopsy-accessible disease are not required to undergo a biopsy as part of 
study participation. 
 
In addition, patients who are being treated with therapeutic doses of anticoagulant(s), are not required 
to undergo a biopsy as part of study participation. If it is felt clinically appropriate despite 
anticoagulation (i.e. a skin punch biopsy, etc) by the treating physician, a biopsy is allowed, it is simply 
not required. 
 
The sites of metastatic disease and reason that the disease is not biopsy-accessible should be 
documented in the medical record and case report form(s). 
 
Patients who do not undergo baseline biopsy must have their study participation approved by the 
overall PI before start of protocol therapy. Only patients who have biopsy inaccessible disease may 
enter the study without the requirement for baseline biopsy. 
 
3.1.15 Participants must have normal organ and marrow function as defined below: 
• Absolute neutrophil count > 1,500/mcL  
• Platelets > 100,000/mcL  


 
 
 
Page | 23  
• Hgb > 9 g/dL (which may be post transfusion)  
• Total bilirubin < 1.5 X institutional upper limit of normal (patients with 
o documented Gilbert’s disease are allowed total bilirubin up to 3X ULN)  
• AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit if no liver metastases; and < 5 X 
institutional upper limit if liver metastases are present.    
• Creatinine < 2X institutional upper limit of normal 
• Baseline QTc < 480 ms 
 
3.1.16  Ability to take oral medications. 
 
3.1.17 The effects of palbociclib and bazedoxifene on the developing human fetus are unknown. If, for any 
reason, a woman should become pregnant or suspect that she is pregnant while participating in this 
study, she should inform her treating physician immediately.  
 
Women who are made postmenopausal through use of GNRH agonists, and men are required to use 
adequate contraception for the duration of protocol treatment and for 6 months after the last dose of 
palbociclib and bazedoxifene. Adequate contraception is defined as one highly effective non-hormonal 
form of contraception or two effective forms of non-hormonal contraception by the patient and/or 
partner. 
 
Highly Effective Non-Hormonal Contraception Methods of birth control which result in a low 
failure rate (i.e., less than 1% per year) when used consistently and correctly are considered highly-
effective forms of contraception. The following non-hormonal methods of contraception are acceptable:  
• True abstinence when this is in line with the preferred and usual lifestyle of the   patient. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation methods) and 
withdrawal are not acceptable methods of contraception].  
• Male sterilization (with appropriate post-vasectomy documentation of the absence of sperm in 
the ejaculate). For female patients, the vasectomized male partner should be the sole partner. 
 
 
OR 
 
Effective Non-Hormonal Contraception 
Alternatively two of the following effective forms of contraception may be used instead:  
• Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS).  
Consideration should be given to the type of device being used, as there is higher failure rates 
quoted for certain types, e.g., steel or copper wire. 
• Condom with spermicidal foam/gel/film/cream/suppository. 
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. The use of barrier contraceptives should always be 
supplemented with the use of spermicide.  
 
The following should be noted:  
 
• Failure rates indicate that, when used alone, the diaphragm and condom are not highly 
effective forms of contraception. Therefore, the use of additional spermicides does confer 
additional theoretical contraceptive protection.  
• However, spermicides alone are ineffective at preventing pregnancy when the whole ejaculate 
is spilled. Therefore, spermicides are not a barrier method of contraception and should not be 
used alone. 


 
 
 
Page | 24  
 
It should be noted that two forms of effective contraception are required. A double barrier method is 
acceptable, which is defined as condom and occlusive cap (diaphragm or cervical/ vault caps) with 
spermicidal foam/gel/film/cream /suppository. Premenopausal women who have been on a GnRH agonist 
for at least 3 consecutive months prior to study entry are eligible. Women in this group MUST remain on 
the GnRH agonist for the duration of protocol treatment. Such patients should be counseled that GnRH 
agonists alone may not be adequate contraception and that adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study participation should 
be employed. 
 
3.1.18 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Prior treatment with a CDK4/6 inhibitor and/or bazedoxifene. 
 
3.2.2 Participants may not be receiving any other investigational agents. 
 
3.2.3 Concurrent treatment with commercial agents or other agents with the intent to treat the participant’s 
malignancy, including endocrine therapy, chemotherapy, and/or targeted therapy, with the exception of 
bisphosphonates and GnRH agonists, as detailed in sections 3.1.4 and 3.1.9. 
 
3.2.4 Untreated or progressive brain metastases. Patients with treated brain metastases not requiring chronic 
corticosteroids for symptom control are eligible. 
 
3.2.5 Pending visceral crisis, in the opinion of the treating investigator. 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic  
    
composition to palbociclib and /or bazedoxifene. 
 
3.2.7 Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A 
isoenzymes are ineligible. Lists including medications and substances known or with the potential to 
interact with the CYP3A isoenzymes are provided in Appendix C. Because the lists of these agents are 
constantly changing, it is important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians’ 
Desk Reference may also provide this information. As part of the enrollment/informed consent 
procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if 
new medications need to be prescribed or if the patient is considering a new over-the-counter medicine 
or herbal product. 
 
3.2.8 Current use of drugs that are known to prolong the QT interval (See Appendix B) 
 
3.2.9 Subjects with organ allograft requiring immunosuppression. 
 


 
 
 
Page | 25  
3.2.10 Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. Ability to comply with study 
requirements is to be assessed by each investigator at the time of screening for study participation. 
 
3.2.11 Pregnant women are excluded from this study because effects of palbociclib and bazedoxifene on a 
developing fetus is unknown. Breastfeeding should be discontinued prior to entry onto the study. 
 
 
3.2.12 Individuals with a history of a different malignancy are ineligible except for the following 
circumstances. Individuals with a history of other malignancies are eligible if they have been disease-
free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that 
malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 
years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell 
carcinoma of the skin. 
 
3.2.13 Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are ineligible because of 
the potential for pharmacokinetic interactions or significant immunosuppression with Palbociclib. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.  Every effort will be made to 
include patients from minority populations. 
 
4. REGISTRATION AND RECRUITMENT PROCEDURES 
 
4.1 
Recruitment Procedures 
 
To enhance accrual and awareness of the trial, the study team will review clinic schedules and patient lists of 
medical oncologists at DF/HCC to identify eligible patients with hormone receptor positive breast cancer. 
 
Providers will be contacted about any patients identified through this procedure and given the opportunity to 
consider this patient for treatment on trial, and subsequently approach the patient about participating in the trial. 
 
4.2 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for Clinical Trials 
(QACT) central registration system. Registrations must occur prior to the initiation of protocol therapy. Any 
participant not registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the QACT 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause treatment delays 
should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol 
therapy following registration, the participant’s registration on the study must be canceled. Notify the QACT 
Registrar of registration cancellations as soon as possible.  
 
4.3 
Registration Process for DF/HCC and DF/PCC Institutions 
 


 
 
 
Page | 26  
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM Eastern 
Standard Time. In emergency situations when a participant must begin protocol therapy during off-hours or 
holidays, call the QACT registration line at 617-632-3761 and follow the instructions for registering 
participants after hours. 
 
The registration procedures are as follows: 
 
• Obtain written informed consent from the participant prior to the performance of any protocol specific 
procedures or assessments.  
 
• Complete the QACT protocol-specific eligibility checklist using the eligibility assessment documented 
in the participant’s medical record and/or research chart. To be eligible for registration to the 
protocol, the participant must meet all inclusion and exclusion criterion as described in the 
protocol and reflected on the eligibility checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a treatment 
protocol. Registration to both treatment and ancillary protocols will not be completed if eligibility 
requirements are not met for all studies.  
 
• Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-632-2295. For 
Phase I protocols, attach participant dose level assignment confirmation from the sponsor. 
 
• The QACT Registrar will (a) review the eligibility checklist, (b) register the participant on the protocol, 
and (c) randomize the participant when applicable. 
 
• An email confirmation of the registration and/or randomization will be sent to the Overall PI, study 
coordinator(s) from the Lead Site, treating investigator and registering person immediately following the 
registration and/or randomization. 
 
5. TREATMENT PLAN 
 
Bazedoxifene and palbociclib will be supplied every 4 weeks, with 28 consecutive days defined as a treatment 
cycle. Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as well as 
dose modifications for palbociclib are described in Section 6 (Expected Toxicities and Dosing Delays/Dose 
Modification). No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 
 
The safety run-in phase of the study will include six patients. If more than 1 of 6 patients has a dose limiting 
toxicity the dose will be reduced to 100 mg for the remainder of the study. Accrual to the study will be paused 
for official safety analysis after all six patients complete at least one treatment cycle. 
 
 
 
 
 
 
 
 
 


 
 
 
Page | 27  
5.1 
Treatment Regimen 
 
Regimen Description 
Agent 
Premedication; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Palbociclib 
Given with food 125 mga 
PO 
Daily on 
days 1-21, 
followed 
by one 
week off 
28 days  
(4 weeks) 
 
 
 
Bazedoxifene 
None 
40mg 
PO 
Daily, 
Continuous 
 a. If more than 1 of 6 patients has a dose limiting toxicity in the safety run, the dose will be reduced to 100mg 
for the remainder of the study. 
 
5.2 
Pre-Treatment Criteria 
 
Informed consent will be obtained after the study has been fully explained to the subject and before the conduct 
of any screening procedures or assessments. If screening assessments occur within 3 days before start of study 
treatment, then they may serve as the baseline Cycle 1 Day 1 study tests. 
 
Pretreatment criteria will be assessed within 14 days of the first dose of study treatment to establish eligibility 
and baseline values. This will be considered the baseline clinical evaluation. Subsequent changes from 
screening physical exam (PE) findings that meet the definition of an AE will be recorded on the AE page of the 
eCRFs. 
 
Demographic information and baseline characteristics will be collected at the Screening Visit. Standard 
demographic parameters include age, sex, and race/ethnicity (recorded in accordance with prevailing 
regulations). Baseline characteristics will include ECOG PS (Appendix A), disease status, medical histories, 
prior and concomitant medications, and PE findings. Relevant hormone receptor status will be collected. 
 
Additional pre-treatment evaluations, also found in section 3.1, are CBC with differential, chemistries, and 
EKG.  
 
Required results for initiation of protocol therapy include: 
• Absolute neutrophil count > 1,500/μL 
• Platelets > 100,000/μL 
• Hemoglobin > 9g/dL 
• Total bilirubin < institutional upper limit of normal (patients with documented Gilbert’s disease are 
allowed total bilirubin up to 1.5X ULN) 
• AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal 
• Creatinine within normal institutional limits or creatinine clearance > 60 mL/min/1.73 m2 for subjects 
with creatinine levels above institutional normal. 
• Baseline QTc < 480 ms 
• Pregnancy test for women on a GNRH analog. 
• FSH and estradiol for women <60 who have had amenorrhea for 12 or more months (in the absence of 
chemotherapy, tamoxifen, toremifen, or ovarian suppression) 
 


 
 
 
Page | 28  
 
5.3 
Agent Administration 
 
5.3.1 Palbociclib 
 
Palbociclib 125 mg should be taken orally, once per day, with food. If a dose is vomited, a replacement dose 
should NOT be taken. If a dose is missed, and it is less than 6 hours from usual time of dosing, then patients 
may take that dose. Otherwise that dose should be skipped and NOT retaken; patients should resume regular 
dosing the following day.  Patients who inadvertently take 1 extra dose during a day must skip the next day’s 
dose.  Patients should be instructed to record daily administration of the study drugs in a drug diary  
(Appendix D). Treatment is continuous daily for 21 days, and then 7 days off, to complete a 28 day cycle.  
 
On days when patient is scheduled for a clinic visit, the patient may take the oral medications at home or in the 
clinic. In addition, patients will bring pill bottles to visits, and pill counts will be performed as follows: Patients 
will be required to return all bottles of palbociclib as well as the completed drug diary at each study visit for 
drug accountability. Drug accountability for palbociclib will be performed at each study visit prior to dispensing 
drug supply for the next cycle(s). The number of remaining capsules/tablets will be documented and recorded. 
 
To be considered compliant, each study patient must have taken at least 80% of the planned number of doses of 
primary therapy based on the number of days of actual dose administration. 
 
5.3.2 Bazedoxifene 
 
Bazedoxifene 40mg (2 tabs of 20mg) should be taken orally, once per day.  If a dose is vomited, a replacement 
dose should NOT be taken.  If a dose is missed, and it is less than 6 hours from usual time of dosing, then 
patients may take that dose.  Otherwise that dose should be skipped and NOT retaken; patients should resume 
regular dosing the following day.  Patients who inadvertently take 1 extra dose during a day must skip the next 
day’s dose.  Patients should be instructed to record daily administration of the study drugs in a drug diary 
(Appendix D). 
 
Treatment is continuous daily to complete a 28 day cycle. Ordering of bazedoxifene self-administration relative 
to palbociclib self-administration is as per patient preference. 
 
On days when patient is scheduled for a clinic visit, the patient may take the oral medications at home or in the 
clinic. 
 
In addition, patients will bring pill blister cards to visits, and pill counts will be performed as follows: Patients 
will be required to return all blister cards of bazedoxifene as well as the completed drug diary at each study visit 
for drug accountability. Drug accountability for bazedoxifene will be performed at each study visit prior to 
dispensing drug supply for the next cycle(s). The number of remaining capsules/tablets will be documented and 
recorded. 
 
To be considered compliant, each study patient must have taken at least 80% of the planned number of doses of 
primary therapy based on the number of days of actual dose administration. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
All prior treatment or medication administered during the 30 days preceding the first dose of study treatment 
and any concomitant therapy administered to the subject throughout the study until 30 days after the final dose 
of study treatment must be recorded on the Prior and Concomitant Therapy page of the eCRF. The generic 


 
 
 
Page | 29  
name of the drug (or trade name for combination drugs) must be specified along with the duration of treatment 
and indication for use. If concomitant medication/therapy is administered for an adverse event (AE), 
investigators will record that AE on the AE page of the eCRF. 
 
Supportive care medications are allowed at any time on trial. Specifically, the following agents are permitted: 
• Antiemetics 
• Antidiarrheal therapy 
• Antiallergic measures such as corticosteroids and antihistamines 
• Agents to assist in the management of hot flashes or headaches (NSAIDs, gabapentin, duloxetine, 
venlafaxine, citalopram, etc) 
• Treatment with either a bisphosphonate or denosumab when bone lesions are documented (as non-target 
lesions) is allowed for the treatment of bone metastases. The first dose should be given prior to the start 
of protocol therapy. Oral bisphosphonate treatment is allowed for patients with a low bone mineral 
density. Patients already receiving bisphosphonate at the time of study entry can continue the treatment. 
• Growth Factors: Patients may receive erythropoietin while on study, at the discretion of the patient’s 
treating physician. The use of G-CSF/GM-CSF should generally be limited to clinical scenarios such as 
febrile neutropenia or active infection, and should not be administered on a chronic basis to maintain 
neutrophil counts as part of ongoing therapy. The use of platelet growth factors are specifically 
prohibited on this protocol. Please consult the Principal Investigator with questions. Investigational 
growth factors are not permitted on this study. 
 
The use of concurrent investigational or other antitumor therapies is not permitted. Missed doses of either 
endocrine therapy or palbociclib are not made up. 
 
Strong CYP3A inhibitors/inducers are not allowed on study. Palbociclib is metabolized to multiple metabolites 
in a qualitatively similar manner in rat, dog and human liver microsomes. In vitro, Palbociclib is primarily 
metabolized by CYP3A4 enzymes. Co-administration with drugs that are CYP3A inhibitors and inducers may 
change the plasma concentrations of palbociclib in humans. The concurrent use of CYP3A inhibitors, including 
amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, 
fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit, grapefruit 
juice or any product containing grapefruit, are not allowed in the study. The concurrent use of CYP3A inducers, 
including carbamazepine, felbamate, nevirapine, phenytoin, primidone, rifabutin, rifampin, rifanpicin, 
rifapentin, and St. John’s wort, are not allowed in the study. This medication list may also be found in 
Appendix C. 
 
Concomitant use of moderate CYP3A inducers and CYP3A substrates is allowable on study, however 
precaution should be exercised for use of any concomitant medication. 
 
Uridine diphosphate glucuronosyltransferase (UGT) inducers are not allowed in this study. Bazedoxifene is a 
UGT substrate. Co-administration with drugs that are UGT inducers may change the plasma concentrations of 
bazedoxifene. The concurrent use of the UGT inducers carbamazepine, dabrafenib, eslicarbazepine acetate, 
phenobarbital, phenytoin and rifampin are not allowed in the study. 
 
The use of herbal medicine is not recommended during protocol treatment. 
 
Surgery is allowed during protocol therapy, however it is suggested to avoid nadir of counts at time of surgery. 
Patients pursuing surgery must hold palbociclib and bazedoxifene therapy 7 days before the surgery and up to 3 
weeks after surgery. Patients may resume palbociclib and bazedoxifene therapy once satisfactory wound healing 
and recovery have occurred.  


 
 
 
Page | 30  
 
Proton pump inhibitors (PPI) may be taken while on study, however it is recommended that the PPI is taken 
12 hours from the time of palbociclib administration. If needed, alternative antacid therapies may be used 
including H2-receptor antagonists and locally acting antacids. H2-receptor antagonists should be administered 
with a staggered dosing regimen (twice daily). The dosing of palbociclib should occur at least 10 hours after 
H2-receptor antagonist evening dose and 2 hours before the H2-receptor antagonist morning dose. Local antacid 
should be given at least 2 hours before or after palbociclib administration. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In the 
absence of treatment delays due to adverse events, treatment may continue until one of the following criteria 
applies: 
 
• Disease progression. 
• Intercurrent illness that prevents further administration of treatment. 
• Unacceptable adverse event(s). 
• Participant demonstrates an inability or unwillingness to comply with the oral medication regimen 
and/or documentation requirements. 
• Participant decides to withdraw from the study. 
• General or specific changes in the participant's condition render the participant unacceptable for further 
treatment in the opinion of the treating investigator. 
 
At the time the patient is taken off study treatment, alternative care options will be discussed with the 
participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from protocol 
therapy. This form can be found on the QACT website or obtained from the QACT registration staff. 
 
In the event of unusual or life-threatening complications, participating investigators must immediately notify the 
Principal Investigator, Dr. Rinath Jeselsohn at 617-632- 3352, pager #42912 (Email: rjeselsohn@partners.org). 
 
5.6 
Duration of Follow Up 
 
Participants will be followed approximately every 4 months for up to 2 years after going off treatment or until 
death, whichever occurs first. Participants who have been taken off treatment for unacceptable adverse events 
will be followed at least until resolution or stabilization of the adverse event. 
 
5.7 
Criteria for Removal from Study Follow-up  
 
Participants will be removed from follow up when any of the criteria listed in Section 5.5 applies. The reason 
for removal from study follow up and the date the participant was removed must be documented in the study-
specific case report form (CRF). 
 
Participants who are removed from study treatment will continue to be followed for long-term outcomes for up 
to 2 years as specified in Section 5.6. 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 


 
 
 
Page | 31  
• Death 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from study. This 
form can be found on the QACT website or obtained from the QACT registration staff. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for dose delays and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
All adverse events experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and until 30 days after removal from study or death, whichever occurs first. 
Participants continuing to experience toxicity at the off study visit may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible. 
 
6.1 
Toxicity Management 
 
6.1.1 Toxicity management – Palbociclib 
 
Every effort should be made to administer study treatment on the planned dose and schedule. 
However, in the event of significant treatment-related toxicity, administration of palbociclib may need to be 
adjusted as described in section 6.2.3. In the event treatment interruption is deemed necessary for either 
palbociclib or the endocrine therapy, treatment with the other medication will continue as planned. 
 
If the retreatment parameters (see section 6.2.1) are met within 3 weeks of treatment interruption or cycle delay, 
palbociclib may be resumed. Please refer to Dose Reductions Section for adverse events requiring dose 
reduction at the time of treatment resumption. 
 
If the retreatment parameters have not been met after 3 weeks of dose interruption (including the scheduled 1 
week off treatment), the patient should permanently discontinue palbociclib and bazedoxifene treatment. 
 
Patients discontinuing palbociclib and/or bazedoxifene treatment due to treatment-related toxicity will come off 
study. 
 
6.1.2 Toxicity management – Bazedoxifene 
 
No dose reduction for bazedoxifene is permitted, but dosing interruptions are allowed (see section 6.2). 
Treatment interruptions for up to 3 cumulative weeks for bazedoxifene related toxicities or personal reasons are 
allowed as per the investigator’s best medical judgment. Patients discontinuing due to treatment-related toxicity 
will discontinue protocol therapy and come off study.  
 
6.2 
Dose Modifications/Delays 
 
In the event of significant treatment-related toxicity, palbociclib dosing may be interrupted or delayed and/or 
reduced as described below. In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed. Patients are to be instructed to notify Investigators at the first occurrence of any adverse sign 
or symptom. 


 
 
 
Page | 32  
 
6.2.1 Palbociclib Dosing Interruptions/Delays 
 
Patients experiencing the following adverse events should have their treatment of palbociclib 
interrupted/delayed until criteria for retreatment are met: 
• Uncomplicated Grade 3 or 4 neutropenia (ANC<1000/mm3); 
• Grade 3 or 4 neutropenia (ANC<1000/mm3) associated with a documented infection or 
• fever ≥38.5°C, 100.4°F; 
• Grade 2 or higher thrombocytopenia (Platelet <75,000/mm3); 
• Grade ≥3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and 
• hypertension only if persisting despite optimal medical treatment); 
• Grade 2 non-hematologic toxicity persisting despite optimal medical treatment and 
• lasting more than 3 weeks; 
• Grade 3 QTc prolongation (QTc ≥501 msec on at least two separate ECGs); 
• In case of concurrent > 3x ULN ALT and 2x ULN Total Bilirubin, palbociclib and bazedoxifene will be 
permanently discontinued. 
 
Patients should not hold or discontinue palbociclib for side effects potentially or likely related to concomitant 
bazedoxifene as per the investigator’s judgment.  Appropriate follow up assessments should be performed until 
adequate recovery occurs as assessed by the Investigator before treatment can resume. 
 
Missed doses are not made up. When the adverse event resolves, the cycle will continue as scheduled. The need 
for a dose reduction at the time of treatment resumption should be based on the criteria defined in Dose 
Reductions Section unless expressly agreed otherwise following discussion between the investigator and the 
principal investigator. If a dose reduction is applied, the patient may need to return to the clinic to receive new 
drug supply. 
 
6.2.2 Palbociclib Retreatment criteria 
 
Retreatment with palbociclib following treatment interruption for treatment related toxicity or at the start of any 
new cycle may not occur until all of the following parameters have been met: 
• Platelet count ≥75,000/mm3 
• ANC ≥1000/mm3 and no fever 
• Any persistent grade 2, grade 3 or higher treatment-related non-hematologic AEs considered related to 
palbociclib have recovered to Grade ≤ 1 or baseline. 
• Only if treatment was held for QTc prolongation: QTc <480 msec and potential reversible causes (eg, 
electrolyte imbalance, concomitant medications known to prolong QTc) corrected. If QTc remains 
above 480 msec, cardiology should be consulted and the ECG be monitored more frequently as per the 
investigator’s best medical judgment until QTc ≤480 msec. 
 
If a treatment delay results from decline in hematologic parameters, the frequency of blood count assessments 
should be adjusted as clinically indicated. If the retreatment parameters are met within 3 weeks of treatment 
interruption or cycle delay, palbociclib may be resumed. Please refer to Dose Reductions Section for adverse 
events requiring dose reduction at the time of treatment resumption.  
 
Cycles should be 28 days long even if the start of a new cycle is delayed. 
  


 
 
 
Page | 33  
Doses missed within a cycle are not made up.  If the adverse event resolves before the end of the cycle then the 
patient can resume taking the Palbociclib for the remainder of the cycle but should still stop on Day 21 to 
maintain the 7- day break.   
The start of a new cycle should be delayed if an adverse event requiring a dose hold has not resolved by Day 1.   
 
The need for a dose reduction at the time of treatment resumption should be based on the criteria defined in 
Dose Reductions Section unless expressly agreed otherwise following discussion between the investigator and 
the principal investigator.  If a dose reduction is applied, the patient may need to return to the clinic to receive 
new drug supply. 
If these parameters have not been met after 3 weeks of dose interruption (including the scheduled 1 week off 
treatment), the patient should be removed from the study. 
 
6.2.3 Dose Reductions 
 
Following dose interruption or cycle delay the palbociclib dose may need to be reduced when treatment is 
resumed. 
 
No specific dose adjustments are recommended for Grade 1 or short lasting Grade 2 (<3 weeks) treatment-
related toxicity. However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances. 
 
In case of a Grade 2 toxicity lasting for >3 weeks or a Grade 3 toxicity (both assessed in the presence of 
maximum supportive care as judged by the investigator), dose reduction is recommended for the subsequent 
cycles. Taking palbociclib according to recommendation (i.e., with food) should be reinforced and confirmed. 
Dose reduction of palbociclib by one dose level, and, if needed, by two dose levels (Table 1) may be 
recommended depending on type and severity of the toxicity encountered. Once a dose has been reduced for a 
given patient, all subsequent cycles should be administered at that dose level, unless further dose reduction is 
required. Dose re-escalation is not allowed. Patients requiring more than 2 dose reductions will be discontinued 
from the study. 
 
Table 1. Dose Levels 
 
Dose Level 
Palbociclib for 3 out of 4 weeks (3/1 schedule) 
Starting dose  
125 mg /day 
-1 
100mg/day 
-2 
75 mg/day 
 
Discontinue study treatment 
 
Palbociclib recommended dose modifications for treatment-related toxicities requiring treatment 
interruption/delay or persisting despite optimal medical treatment are described in Table 2. 
 
Toxicity 
Management/Next Dose for Palbociclib 
Uncomplicated Grade 3 
neutropenia 
(ANC ≥500 - <1000/mm3) 
• 1st occurrence: Hold drug. If ANC recovers (ANC ≥ 1000) within 2 
  weeks, resume at same dose.  
• If ANC takes longer than 2 weeks to recover (ANC ≥1000), but within 3 
weeks, then resume drug and decrease drug by 1 dose level. 
• Recurrent uncomplicated Grade 3: Hold drug. If ANC recovers (ANC ≥ 
  1000) within 2 weeks, resume drug and decrease drug by 1 dose level. 


 
 
 
Page | 34  
Toxicity 
Management/Next Dose for Palbociclib 
Grade 3 neutropenia 
(ANC<1000/mm3) 
associated with a 
documented infection 
or fever >38.5° C,100.4° F 
• Hold drug. If ANC recovers (ANC ≥ 1000) within 2 weeks, resume drug 
  and decrease drug by 1 dose level. 
• If ANC takes longer than 2 weeks to recover (ANC ≥1000), but within 3 
  weeks, then resume drug and decrease drug by 2 dose levels. 
• If these parameters have not been met after 3 weeks of dose 
interruption (including the scheduled 1 week off treatment), the patient 
should permanently discontinue Palbociclib. 
Grade 4 neutropenia 
(ANC < 500/mm3) 
• First occurrence: Hold drug. Resume once ANC > 1000 and decrease 
  dose by 1 dose level. 
• Recurrent Grade 4 neutropenia: Hold drug. Resume once ANC > 1000 
  and decrease dose by an additional dose level. 
Grade 3 or 4 
thrombocytopenia 
(platelet count < 50,000)  
• 1st occurrence: Hold drug until plt > 100,000, then resume drug and 
  decrease by 1 dose level. 
• Recurrent Grade 3 thrombocytopenia: hold drug until plt >100,000, then 
  decrease drug by an additional dose level. 
Grade ≥3 non-hematologic 
toxicity 
(including, nausea, vomiting, 
diarrhea, and hypertension only if 
persisting despite optimal medical 
treatment); 
• 1st occurrence: Hold drug until toxicity decreases to < Grade 1 or to 
  baseline, then resume drug and decrease by 1dose level. 
• If toxicity takes longer than 2 weeks to recover to < Grade 1, but within 3 
  weeks, then resume drug and decrease drug by 2 dose levels.  
• Recurrent toxicity: Hold drug until toxicity decreases to < Grade 1 or to 
  baseline, then decrease drug by an additional dose level. 
Grade 2 non-hematologic 
toxicity persisting despite 
optimal medical treatment, 
deemed unacceptable in the 
investigator’s judgment, 
and lasting at least 2 weeks 
• 1st occurrence: Hold drug until toxicity decreases to < Grade 1 or to 
  baseline, then resume drug at same dose level. 
• Recurrent toxicity: Hold drug until toxicity decreases to < Grade 1 or to 
 baseline, then resume drug and decrease by 1 dose level. 
LFTs 
SGPT/ALT > 3X ULN SGPT/ALT 
and 2X ULN total bilirubin 
Discontinue study treatment permanently. 
 
QTc prolongation management 
In the event of QTc prolongation, possible alternative reversible causes such as serum electrolytes 
abnormalities, or usage of concomitant medications with the potential to prolong the QTc interval should be 
evaluated. If such reversible causes are identified, then they should be corrected accordingly (i.e., correction of 
electrolyte abnormalities with supplements to within normal limits and/or discontinuation (if possible) of 
concomitant medications known to prolong the QT interval (see Appendix B). 
 
Recommended dose modifications in the event of QTc prolongation are provided in the Table below.  
 
Palbociclib Dose Modifications in the Event of QTc Prolongation 
 
 
Grade 2 QTc prolongation 
 (>480 and <500 msec, or 60 
msec above baseline) 
 
Grade 3 QTc prolongation 
(≥ 501 msec) 
Grade 4 QTc 
prolongation 
(≥ 501 msec or >60 ms 
change from baseline and 
life threatening signs 
including Torsades de 
points) 


 
 
 
Page | 35  
Reversible 
cause 
identified 
Treat reversible cause 
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc ≤ 480 
msec 
Continue at the same dose 
level (1) 
Treat reversible cause 
Withhold treatment until 
QTc <500 msec 
Resume treatment at the 
same dose level. 
Monitor ECG more 
frequently as per 
investigator’s best medical 
judgment until QTc ≤ 480 
msec. 
Permanently 
discontinue 
No 
reversible 
cause 
identified 
Consult cardiology and 
initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc ≤ 480 
msec; 
Continue at the same dose 
level (1) 
Withhold treatment until 
QTc <500 msec 
Resume treatment at the next 
lower dose level (2) 
 Consult cardiology and 
monitor ECG more 
frequently as per 
investigator’s best medical 
judgment until QTc ≤ 480 
msec. 
Permanently 
discontinue 
 
1. If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the absence of 
other alternative causes or despite correction of alternative causes, dose adjustment and/or discontinuation should be 
considered in consultation with a cardiologist and the study medical monitor, taking into account the emerging 
safety data from palbociclib trials and the investigator’s best medical judgment. 
 
2. If the Grade 3 QTc prolongation occurs again after one dose reduction, further dose adjustment and/or 
discontinuation should be discussed with study medical monitor in consultation with a cardiologist, taking into 
consideration the emerging safety data from palbociclib trials and the investigator’s best medical judgment. 
 
If the QTc remains at >480 msec for more than 2 cycles or if Grade 2 QTc prolongation recurs in the absence of 
other alternative causes or despite correction of alternative causes, dose adjustment and/or discontinuation should be 
considered in consultation with a cardiologist and the study monitor. 
 
6.2.4 Bazedoxifene dose modifications/delays 
  
No dose reduction for bazedoxifene is permitted, but dosing interruptions are allowed. If bazedoxifene -related 
adverse events occur, they should be managed using standard clinical practice (e.g. hot flashes can be treated 
with venlafaxine). 
 
If grade 3 or 4 toxicity occurs that the treating investigator feels is related to bazedoxifene, the study Principal 
Investigator should be contacted to discuss the case and determine whether continuation of protocol therapy is 
appropriate.  
 
Treatment interruptions for up to 3 cumulative weeks for bazedoxifene therapy-related toxicities or personal 
reasons are allowed as per the investigator’s best medical judgment. Palbociclib should not be held during 
bazedoxifene therapy interruption, unless palbociclib is on hold for a separate reason as described in section  
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of 


 
 
 
Page | 36  
reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting. 
 
7.1 
Adverse Events Lists 
 
7.1.1 Expected Toxicities for Palbociclib 
 
The primary anticipated toxicity of palbociclib is neutropenia. In the phase I, dose-escalation trial of palbociclib 
alone in advanced cancers, neutropenia was the only dose-limiting toxicity (DLT). Grade 3 neutropenia during 
cycle 1 was observed in 3/22 patients receiving palbociclib 125 mg PO daily, with no grade 4 neutropenic 
events observed. Based on this result, 125 mg PO daily became the recommended phase 2 dose (RP2D). Other 
hematologic AEs of grade 3 or greater during cycle 1 were anemia and leukopenia, occurring in 1 and 4 of 41 
patients, respectively. The most common non-hematologic AEs of grade 3 or greater during cycle 1 were 
fatigue, nausea, and abdominal pain (each occurring in 2 of 41 patients). Of note, there were no complicated 
hematologic AEs documented, and all hematologic AEs resolved during the off drug period of a 3 week on/1 
week off schedule, and were non-cumulative. 
 
In a phase II trial of palbociclib alone for advanced breast cancer, the only toxicities > grade 3 observed were 
transient neutropenia (50%) and thrombocytopenia (21%). In a phase II trial of palbociclib plus letrozole for 
first-line therapy of hormone receptor positive breast cancer, the most common AEs reported were neutropenia, 
leukopenia, and fatigue. The median time to first treatment delay for neutropenia was 58 days, and the median 
duration of treatment delay until recovery was 5 days (range 1-16 days). (Pfizer internal data). In general, 
hematologic abnormalities were adequately managed with standard supportive care, were not complicated, 
and resolved during the drug hold with no cumulative toxicity noted. 
 
In the phase I, dose-escalation trial of palbociclib alone in advanced cancers, QT interval changes were also 
evaluated in detail. While 26 of 41 patients had a maximum increase of <30 msec from baseline QTc, zero 
patients had an on-treatment value exceeding 500 msec. 
 
7.1.2 Expected Toxicities for Bazedoxifene 
 
In the two large randomized studies with bazedoxifene in healthy women the most common side effects were: 
hot flashes (20-24% of patients) and muscle cramps (12%). Most cases of hot flashes were mild to moderate 
and did lead to participant discontinuation from study. There were no safety concerns related to the 
cardiovascular system. The number of thromboembolic events was low (<1%) in the bazedoxifene treatment 
arms. There was one death in the bazedoxifene 40 mg group, a subject who experienced a prolonged air flight 
30 days after study completion, was considered by the investigator to be possibly related to treatment. 
 
In the dose escalation study 3 patients (including a patient on the bazedoxifene 5mg dose, 80mg dose and 
placebo) had asymptomatic elevations of ALT levels. In all cases LFTs declined after discontinuation of the 
study drug. 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


 
 
 
Page | 37  
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event varies in 
nature, intensity or frequency from the expected toxicity information which is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the next section 
(Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific Expedited Adverse 
Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting to DF/HCC 
 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the initial 
dose of study treatment, during treatment, or within 30 days of the last dose of treatment on the local 
institutional SAE form.  
 
7.3.2 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4 
Expedited Reporting to Pfizer 
 
Within 24 business hours of first awareness of the event (immediately if the event is fatal or life threatening), 
the Overall PI will report to Pfizer by facsimile or email any Serious Adverse Event (“SAE,” as defined below) 
for which reporting is required under this provision (as described below). Such SAEs are to be reported for 
study subjects or individuals otherwise exposed to the Pfizer Product as described below. The Overall PI should 
report SAEs as soon as they are determined to meet the definition, even if complete information is not yet 
available. 
 
Principal Investigators will report SAEs using Form FDA 3500A (MedWatch). The Reportable 
Event Fax Cover Sheet provided by Pfizer must also be included with each SAE submitted (Appendix H). 
 
7.4.1 SAE Definition for Reporting to Pfizer 
 
An SAE is any adverse event, without regard to causality, that is life-threatening (i.e., causes an 
immediate risk of death) or that results in any of the following outcomes: death; in-patient 
hospitalization or prolongation of existing hospitalization; persistent or significant disability or 
incapacity (i.e. substantial disruption of the ability to conduct normal life functions); or a congenital 
anomaly or birth defect. Any other medical event that, in the medical judgment of the Principal 
Investigator, may jeopardize the subject or may require medical or surgical intervention to prevent one 
of the outcomes listed above is also considered an SAE. A planned medical or surgical procedure is not, 
in itself, an SAE. 
 
7.4.2 Exposure During Pregnancy, Exposure During Lactation, Occupational Exposure 
 


 
 
 
Page | 38  
Even though there may not be an associated SAE, exposure to the Palbociclib and/or bazedoxifene 
during pregnancy, exposure to the Palbociclib and/or during lactation, and occupational exposure to the 
Palbociclib are reportable to Pfizer. 
 
7.4.3 Hy’s Law Cases  
 
Cases of potential drug-induced liver injury as assessed by laboratory test values (“Hy’s Law Cases”) 
are also reportable to Pfizer. If a participant develops abnormal values in aspartate transaminase (AST) 
or alanine transaminase or both, concurrent with abnormal elevations in total bilirubin and no other 
known cause of liver injury, that event would be classified as a Hy’s Law Case. 
 
7.4.4 SAE Reporting Period 
 
The SAEs that are subject to this reporting provision are those that occur from after the first dose of the 
Palbociclib through 30 calendar days after the last administration of the Palbociclib, or longer if so 
specified in the Protocol. In addition, if a Principal Investigator becomes aware of an SAE occurring any 
time after the administration of the last dose of the Palbociclib, the Principal Investigator should report 
that SAE to Pfizer if the Principal Investigator suspects a causal relationship between the Palbociclib 
and the SAE. 
 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall PI will 
report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the FDA’s criteria 
for expedited reporting following the reporting requirements and timelines set by the FDA. 
 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety reports or 
sentinel events that require reporting according to institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the toxicity case 
report forms.  AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also 
be reported in routine study data submissions. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents administered in this 
study can be found in Section 7.1. 
 
8.1 
Palbociclib 
 
8.1.1 Description 
 
Chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino) pyrido[2,3-
d]pyrimidin-7(8H)-one. 
Chemical formula: C24H29N7O2 
Molecular weight: 447.54. 


 
 
 
Page | 39  
Half life: ~29 hours. 
Plasma protein binding of palbociclib: ~85% 
Plasma protein binding of PF-05089326 (the lactam of palbociclib, one of the main metabolites present 
in plasma): 95% 
 
Palbociclib (IC50 = 11 nM; Ki = 2 nM) is metabolized to multiple metabolites in a qualitatively similar 
manner in rat, dog and human liver microsomes. In vitro, Palbociclib is primarily metabolized by 
CYP3A4 and SULT2A1 enzymes. Information on potential drug interactions can be found in section 
5.4. 
 
8.1.2 Form 
 
Palbociclib will be supplied by Pfizer as capsules containing 75 mg, 100 mg, or 125 mg equivalents of 
palbociclib free base. Pfizer will supply the oral drug formulation to sites in High Density Polyethylene 
(HDPE) bottles containing 75 mg, 100 mg, or 125 mg capsules. The capsules can be differentiated by 
their size and color (see below). 
 
 
Table 4. Palbociclib Capsule characteristics 
Dosage 
Capsule Color 
Capsule Size 
75mg 
Sunset Yellow 
2 
100mg  
Caramel/Sunset Yellow 
1 
125mg 
Caramel 
0 
 
 
8.1.3 Storage and Stability 
 
Storage conditions stated in the Single Reference Safety Document (i.e. Investigator’s Brochure (IB), 
United States Package Insert (USPI), Summary of Product Characteristics (SPC), or Local Product 
Document (LPD)) will be superseded by the label storage. 
 
Palbociclib capsules should be stored at controlled room temperature (15-30°C, 59-86°F) in their 
original container. 
 
Investigators and site staff are reminded to check temperatures daily (i.e. manually or by using alarm 
systems to alert of any excursions) and ensure that thermometers are working correctly as required for 
proper storage of investigational products. These include thermometers for room storage. Any 
temperature excursions must be reported to Pfizer. The investigational products must be stored as 
indicated. Deviations from the storage requirements, including any actions taken, must be documented 
and reported to Pfizer. 
 
Once a deviation is identified, the investigational products (palbociclib) must be quarantined and not 
used until Pfizer provides documentation of permission to use the investigational product. 
 
Medication should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Returned medication should be stored separately from medication that needs to 
be dispensed. 
 
8.1.4 Compatibility 
 


 
 
 
Page | 40  
No compatibility issues exist for co-administration of palbociclib and bazedoxifene. 
 
8.1.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic 
agent in a self-contained and protective environment.  
 
8.1.6 Availability 
 
Palbociclib will be provided from the commercial supply and will be supplied free-of-charge from 
Pfizer. 
 
8.1.7 Administration 
 
Palbociclib will be provided in non-patient-specific bottles containing either 75 mg, 100 mg or 125 mg 
capsules. 
 
The patient number should be recorded on the bottle label in the spaces provided by site personnel at the 
time of assignment to patient. Site personnel must ensure that patients clearly understand the directions 
for self-medication. Patients should be given a sufficient supply to last until their next study visit. 
Unused drug and/or empty bottles should be returned to the site at the next study visit. Unused returned 
medication MUST NOT be re-dispensed to patients. 
 
Palbociclib is an agent that must be handled and administered with care. Patients should be instructed to 
keep their medication in the bottles provided and not transfer it to any other container. Due to possible 
unknown hazards associated with topical and environmental exposure to experimental agents, capsules 
must not be opened and/or emptied into any vehicle for oral ingestion; capsules must be swallowed 
intact. 
 
Only a single capsule strength will be dispensed to the patient at each dispensing visit. In the event of 
dose modification, request should be made of the patient to return all previously dispensed medication to 
the clinic and new capsules will be dispensed. 
 
8.1.8 Ordering 
 
Qualified personnel at participating sites will order the drug directly from Pfizer. The Drug Supply 
Request Form is in Appendix F. 
 
8.1.9 Accountability 
 
To ensure adequate records, palbociclib capsules will be accounted for as instructed by Pfizer. Patients 
are requested to return previously dispensed containers as well as their completed drug diary to the clinic 
at each visit for accountability purposes even if they will not be issued with new medication at that visit. 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful record 
of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) 
or another comparable drug accountability form.  (See the NCI Investigator’s Handbook for Procedures 
for Drug Accountability and Storage.) 
 


 
 
 
Page | 41  
8.1.10 Destruction and Return 
 
Sites will document and destroy unused investigational product per their local policies. The site primary 
investigator must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer. Destruction must be 
adequately documented. 
 
8.2 
Bazedoxifene 
 
8.2.1 Description 
 
Chemical name: Chemical name: 1-{p-[2-(Hexahydro-1H-axepin-1-yl)ethoxy]benzyl}H-2-(p-
hydroxyphenyl)-3-methylindol-5-ol monoacetate 
Chemical formula: C3OH34N2O3,C2H4O2 
Molecular weight: 530.7 
Half life: ~30 hours. 
Plasma protein binding of bazedoxifene : 98%-99% 
Palbociclib (IC50 = 26 nM; Ki = 0.1 nM [ERα])  
Bazedoxifene is absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 
after about 2 hours. Bazedoxifene is absorbed from the gastrointestinal tract, with peak plasma 
concentrations occurring after about 2 hours. Bazedoxifene-5-glucuronide is the major circulating 
metabolite. It is expected to undergo enterohepatic recycling. Information on potential drug interactions 
can be found in section 5.4. 
 
8.2.2 Form 
 
Bazedoxifene will be supplied by Pfizer as tablets containing 20mg.  
 
8.2.3 Storage and Stability 
 
Storage conditions stated in the Single Reference Safety Document (i.e., Investigator’s Brochure (IB), 
United States Package Insert (USPI), Summary of Product Characteristics (SPC), or Local Product 
Document (LPD) will be superseded by the label storage. 
 
Bazedoxifene should be stored at 20-25°C (68-77°F), excursions permitted to 15°C to 30°C (59°F to 
86°F) in their original container. 
 
Investigators and site staff are reminded to check temperatures daily (i.e. manually or by using alarm 
systems to alert of any excursions) and ensure that thermometers are working correctly as required for 
proper storage of investigational products. These include thermometers for room storage. Any 
temperature excursions must be reported to Pfizer. The investigational products must be stored as 
indicated. Deviations from the storage requirements, including any actions taken, must be documented 
and reported to Pfizer. 
 
Once a deviation is identified, the investigational products (bazedoxifene) must be quarantined and not 
used until Pfizer provides documentation of permission to use the investigational product. 
 
Medication should be kept in a secured locked area at the study site in accordance with applicable 
regulatory requirements. Returned medication should be stored separately from medication that needs to 
be dispensed. 


 
 
 
Page | 42  
 
8.2.4 Availability 
 
Bazedoxifene is approved in the European Union for the treatment of post-menopausal osteoporosis in 
women at increased risk of fracture.   It is an investigational agent for the treatment of breast and will be 
supplied free-of-charge from Pfizer. 
 
8.2.5 Administration 
 
Bazedoxifene will be provided in 4 x 7 count blister cards (28 tablets per carton)  containing 20mg 
tablets. 
 
The patient number should be recorded on the carton label in the spaces provided by site personnel at the 
time of assignment to patient. Site personnel must ensure that patients clearly understand the directions 
for self-medication. Patients should be given a sufficient supply to last until their next study visit. 
Unused drug and/or empty blister cards should be returned to the site at the next study visit. Unused 
returned medication MUST NOT be re-dispensed to patients. 
 
8.2.6 Ordering 
 
Qualified personnel at participating sites will order the drug directly from Pfizer. The Drug Supply 
Request Form is in Appendix F. 
 
8.2.7 Accountability 
 
To ensure adequate records, bazedoxifene tablets will be accounted for as instructed by Pfizer. Patients 
are requested to return previously dispensed containers as well as their completed drug diary to the clinic 
at each visit for accountability purposes even if they will not be issued with new medication at that visit. 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using the NCI Drug 
Accountability Record or another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment for the “Policy and Guidelines for Accountability and 
Storage of Investigational Agents” or to obtain a copy of the drug accountability form.) 
 
8.2.8 Destruction and Return 
 
Sites will document and destroy unused investigational product per their local policies. The site primary 
investigator must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer. Destruction must be 
adequately documented. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
The correlative studies are designed to be hypothesis generating. It is anticipated that promising findings will be 
validated in the context of future studies. 
 
9.1 
Research Tissue Specimen Collection 
 


 
 
 
Page | 43  
9.1.1 Tumor tissue will be collected at the following time points on this study: 
 
• When available archival FFPE tissue samples of primary and/or metastatic disease will be retrieved 
preferably within 2 weeks of patient enrollment. Patients who do not have archival FFPE tissue 
samples available will not be required to have a biopsy. 
• Baseline research biopsy to be done up to 2 weeks prior to starting treatment drug:  Required in 
patients with easily accessible or accessible disease, as defined in Section 3.1.14 
• Cycle 1 Day 15 (can be done within a window of +/- 3days) research biopsy: Optional in patients 
with easily accessible disease and accessible disease, as defined in Section 3.1.14 
• Off-study research biopsy to be performed up to 4 weeks after disease progression has been 
determined: Required for patients with easily accessible and optional in patients with accessible 
disease, as defined in Section 3.1.14 
 
Tissue specimens will be collected from tumor lesions using standard institutional procedures. For biopsies 
through the Brigham & Women’s Hospital interventional radiology service, see Appendix E for standard 
operating procedures, amount of tissue to be collected, and processing instructions. If a patient has more than 
one site of disease, only one site needs to be biopsied, and the site is left to the discretion of the patient and her 
treating physician. Core biopsies are required and fine needle aspirates cannot be used. Patients who undergo an 
attempted research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is 
obtained, are not required to undergo a repeat biopsy in order to continue on protocol.  
 
See Appendix E for additional details regarding research biopsies and processing guidelines. 
 
9.2 
Blood Sample Collection 
 
Blood will be collected for cell-free DNA at baseline and on Day 1 of each cycle. The samples will be 
transferred to the Translational Research Lab, Belfor Institute, for isolation of cell free DNA and droplet digital 
PCR for the detection of ESR1, PIK3CA, GATA3, FOXA1 and NCOR1 mutations.  Refer to Appendix E for 
specimen collection and shipping instructions. 
 
An additional blood sample will be collected for germline DNA at baseline. If for any reason this sample is not 
collected at baseline, it can be collected at another time point during the study.  The blood will be used for DNA 
isolation from white blood cells. Refer to Appendix E for specimen collection and shipping instructions 
 
9.3 
Drug Adherence 
 
Drug diaries (Appendix D) will be maintained for patients to capture adherence to oral palbociclib and 
bazedoxifene therapy. Diaries will be completed prior to each protocol visit and reviewed for accuracy with the 
patient at each visit. Pill counts will be performed and recorded at each study visit by research staff. Optimal 
adherence is defined as >80% of medication taken. Patients found to be non-adherent with their medications 
will receive additional interventions by the treatment team to improve adherence (ie RN phone calls, extra visits 
as needed). If a patient demonstrates persistent non-adherence, their provider may remove them from the trial 
(as described in Section 5.5). 
 
10. STUDY CALENDAR 
 
All subjects must sign an informed consent document prior to initiation of any study related procedures. The 
consenting individual for the clinical trial must be an MD listed as a co-investigator on the trial. 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Scans must be done 


 
 
 
Page | 44  
<4 weeks prior to the start of therapy.   
 
Patients must meet all eligibility requirements prior to research biopsy (when applicable), as outlined in the 
eligibility criterion 3.1.14. 
 
All assessments must be performed prior to administration of any study medication. Day 15 study assessments 
should be performed within + 3 days of the protocol-specified date, unless otherwise noted. Day 1 study 
assessments for Cycle 2 and beyond should be performed within + 3 days of the protocol-specified date.  
Restaging CT or MRI scans and bone scans may be done + 7 days of the protocol-specified date, though it is 
preferred that they occur within the +3 day window if possible. 
 
After patients are taken off protocol treatment, they should be followed for survival every 4 months for up to 2 
years or until time of death, whichever comes first.  If a patient is taken off protocol treatment for any reason 
other than progression or death, then the patient should also be followed for progression with staging scans 
every 8 weeks until disease progression, start of alternative anti- cancer therapy, death, or withdrawal of 
consent, whichever comes first. These patients should also be followed for survival every 4 months for up to 2 
years or until time of death, whichever comes first. 
 
 
Pre- 
Study 
-14 to 0 
days 
C1 
D1 
C1 
D15 
C2 
D1 
C2 
D15 
C3 
D1 
C3 
D15 
D1 of each 
cycle 
Every 2 
cycles 
At time of 
progression or 
off treatment 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X a 
 
X 
 
X 
 
X 
 
X 
Vital signsb 
X 
X a 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X a 
 
X 
 
X 
 
X 
 
X 
ECOG Performance 
statusc 
X 
X a 
 
X 
 
X 
 
X 
 
X 
CBC w/diffd 
X  
X a 
X 
X 
X 
X 
X 
X 
 
X 
Serum chemistrye 
X  
X a 
 
X 
 
X 
 
X 
 
X 
PT,PTTf 
X 
 
Xf 
 
 
 
 
 
 
Xf 
CEA, CA27-29 
X 
 
 
X 
 
 
 
 
X 
 
12-lead EKG  
X 
 
 
X 
 
X 
 
 
X 
 
FSH and estradiolg 
X 
 
 
 
 
 
 
 
 
 
Serum/Urine 
Pregnancy Test           
B-HCGh 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
 
X 
 
X 
 
X 
 
 
Perform pill count 
 
 
 
X 
 
X 
 
X 
 
X 
AE evaluation 
X 
 
 
X 
 
X 
 
X 
 
X 
Tumor measurementsi 
X 
 
 
X 
 
 
 
 
Xj 
 
Bone scank 
X 
 
 
 
 
 
 
 
 
 
Research biopsyl 
X 
 
Xl 
 
 
 
 
 
 
Xl 


 
 
 
Page | 45  
Research blood sample 
Xm 
 
 
X 
 
X 
 
X 
 
X 
Archival tissuen 
 
X 
 
 
 
 
 
 
 
 
Survival  Follow-up 
 
 
 
 
 
 
 
 
 
Xo 
 
a. If performed at baseline < 7 days of C1D1, procedure does not need to be repeated.  In the event that the 
participant's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior 
to initiation of the next cycle of therapy. 
b. Vital signs: heart rate, blood pressure, respiratory rate  
c. See Appendix A for ECOG PS guidelines 
d. CBCs drawn on D15 can be drawn at a local lab.  Lab results are then submitted to study team. 
e. Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose 
(random), total bilirubin, alkaline phosphatase, ALT, AST, albumin, calcium, magnesium, phosphorus.   
f.    PT, PTT if clinically indicated prior to biopsy (-ies) per standard institutional guidelines 
g.   Only applicable for screening, not for subsequent cycle visits, for women age <60 who have had     
amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian      
suppression) 
h.  In women of childbearing potential only (including premenopausal women with intact uterus and 
ovaries on GnRH agonist).  
i.   Baseline tumor assessments should be performed <4 weeks prior to the start of therapy. Radiologic 
imaging studies to evaluate tumor status should be done every 2 cycles +/- 7 days. Contrast computed 
tomography (CT) (or without contrast if contraindicated) of chest and abdomen is preferred. Magnetic 
resonance imaging (MRI) of chest and abdomen is an acceptable alternative. Note: PET-CT scans are 
not allowed per protocol for primary assessment of response. PET-CT scans may be done according to 
clinical judgment to supplement CT or MRI scans in cases where results of the PET-CT may clarify or 
resolve a clinical question. If palpable/visible lesions (e.g. chest wall nodule, etc) is being used as a 
target lesions, measurements and photographs should be taken as well. 
j. After C6, tumor measurements will be performed every 3 cycles.  
k.   A whole body bone scan should be acquired at baseline for all subjects <4 weeks prior to the start of 
therapy. For patients with measurable  disease, skeletal lesions identified on the whole body bone scan at 
baseline, which are not visible on the chest, abdomen and pelvis CT (or MRI) scan should be imaged at 
baseline and followed using localized  CT, MRI or x-ray. Whole body bone scans need not be repeated 
after baseline unless clinically indicated. For patients with bone only disease, whole body scans will be 
performed every 6 months to confirm response, or earlier if clinically indicated. See 11.3.2. 
l.   Baseline research biopsy is required for patients with “easily accessible disease” and “accessible disease” 
(defined in section 3.1.14).  Cycle 1 day 15 research biopsy is optional for patients with “easily 
accessible disease” and “accessible disease”. Off-treatment biopsy is required for patients with “easily 
accessible disease” and is optional for patients with “accessible disease”. 
m.  At the pre-study phase, samples will be collected for cell-free DNA and germline DNA.  At Day 1 of 
cycle 2 and beyond, sample for cell-free DNA will be collected.  Refer to Appendix E for further details. 
n.   Archival tissue can be collected at any time point throughout the study. 
o. Follow-up every 4 months or until death 
 
 
 


 
 
 
Page | 46  
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 2 cycles (1 cycle = 4 
weeks). In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. After cycle 6, tumor measurements will be performed 
every 3 cycles. 
 
Response and progression will be evaluated in this study using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for Objective response.  Only those participants who have measurable disease present at baseline, 
have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for target disease response.  These participants will have their response classified according to the definitions 
stated below.  Bone only disease, if there are lytic lesions, is also allowed and treatment response will be 
evaluated based on the MD Anderson criteria. (Note:  Participants who exhibit objective disease progression 
prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for non-target disease.  The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.  
 
Evaluable for PFS. All participants randomized on this study are considered to be evaluable for PFS    (whether 
or not they are eligible, have measurable disease, or receive protocol therapy). 
 
11.1.2 Disease Parameters 
 
Measurable disease.  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 or ≥10 mm with CT scan, MRI, or 
calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
   A lesion in a previously irradiated area is not eligible for measurable disease unless there is objective evidence 
of progression of the lesion prior to study enrollment. Lesions in previously irradiated areas must be clearly 
identified as such. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
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. 
 


 
 
 
Page | 47  
Non-measurable disease.  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, abdominal masses (not followed by CT or MRI), and cystic lesions are all 
considered non-measurable. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated 
by cross sectional imaging techniques such as CT or MRI can be considered target lesions if the soft tissue 
component meets the definition of measurability as defined above. These lesions will be evaluated by the 
RECIST 1.1 criteria. Lytic bone lesions or mixed lytic-blastic lesions that can be evaluated by cross sectional 
imaging techniques such as CT or MRI can be considered target lesions and response will be evaluated using 
the MD Anderson (MDA criteria) [34]. ‘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 participant, these are preferred for selection as target lesions. Lesions in 
previously irradiated areas or areas subject to other loco-regional therapy are usually not considered measurable 
unless there has been demonstrated progression of that lesion. 
 
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.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 2 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used to assess the anti-tumor effect of a treatment. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers (e.g., skin nodules).  In 
the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended.  
 
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. This applies to 


 
 
 
Page | 48  
tumors of the chest, abdomen, and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols. 
 
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. 
 
Ultrasound (US). When the primary endpoint of the study is objective response evaluation, US should not be 
used to measure tumor lesions. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions, and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination. 
 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should follow the NCI 
Guidelines for using FDG PET as an indicator of therapeutic response (L.K. Shankar, J.M. Hoffman, S. 
Bacharach, M.M. Graham, J. Karp, A.A. Lammertsma, S. Larson, D.A. Mankoff, B.A. Siegel, A. Van den 
Abbeele, J. Yap, D. Sullivan. Consensus recommendations for the use of 18F- FDG PET as an indicator of 
therapeutic response in patients in National Cancer Institute Trials. J Nucl Med, 47(6):901-903, 2006). Patients 
should avoid strenuous exercise and be on a low carbohydrate diet for 24 hours prior to the scan. Patients should 
fast for 4 hours or longer prior to the FDG injection and should have a serum glucose of less than 200 mg/dL at 
the time of FDG injection. A 10-20 mCi dose of FDG should be injected for typical adult patients. For 
longitudinal studies with multiple scans, particular attention should be paid to ensure consistent patient 
preparation and acquisition parameters between the follow-up scan and the baseline scan. When designing a 
study where PET scans are going to be utilized as one of the modalities to evaluate efficacy, it is important to 
consult with physicians in nuclear medicine in designing the appropriate criteria to be utilized. In this protocol, 
PET or PET/CT should NOT be used as the primary modality to evaluate objective response, but may be used in 
an adjunctive fashion together with either CT or MRI in cases of uncertainty, as clinically indicated. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation has not yet been 
fully and widely validated. Their uses in this specific context require sophisticated equipment and a high level 
of expertise that may only be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in reference centers. However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained. In this 
protocol, endoscopy or laparoscopy will not be used for evaluation of response. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a subject to be considered in complete clinical response. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known 
residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment 
when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. 


 
 
 
Page | 49  
11.1.4 Response Criteria  
 
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. 
 
Evaluation of Lytic Bone Lesion Target Lesion (MDA criteria)  
 
Response category 
Criteria 
Complete response 
Complete sclerotic fill-in of lytic lesions on x-ray or CT scan. 
 
Normalization of bone density on x-ray or CT scan. 
 
Normalization of signal intensity on MRI. 
 
Normalization of tracer uptake on skeletal scintigraphy 
Partial Response  
Development of a sclerotic rim or partial sclerotic fill-in of lytic 
lesions on x-ray or CT scan. 
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 x-ray, CT, or MRI. 
≥ 50% subjective decrease in the size of ill-defined lesions on x-ray, 
CT, or MRI. 
≥ 50% subjective decrease in tracer uptake on skeletal scintigraphy. 
Progressive Response 
≥ 25% increase in size of measurable lesions on x-ray, CT, or MRI. 
≥ 25% subjective increase in the size of ill-defined lesions on x-ray, 
CT, or MRI. 
≥ 25% subjective increase in tracer uptake on skeletal scintigraphy. 
New bone metastases. 
 


 
 
 
Page | 50  
 
 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.   
*Measurements are based on the sum of a perpendicular, bidimensional measurement of the greatest  diameters 
of each individual lesion. 
 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD):  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions* (new lesions must be > slice thickness) 
and/or unequivocal progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.     
 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something other than tumor (ex: new 
bone lesions may be healing or flare of pre-existing lesions). However, a lesion identified on a follow-up scan in 
an anatomical location that was not scanned at baseline is considered new and will indicate PD. If a new lesion 
is equivocal (because of small size, etc.), follow-up evaluation will clarify if it truly represents new disease and 
if PD is confirmed, progression should be declared using the date of the initial scan on which the lesion was 
discovered. 
 
Note: If tumor response data is missing for target lesions, the overall assessment must be Unknown (UN) unless 
there is new disease that would result in an overall assessment of PD. However, if there is missing or 
unevaluable data for non-target lesions, but data is available for all target lesions, the overall response for that 
time point will be assigned based on the sum LD of all target lesions. Additionally, the assessment of CR cannot 
be made if there is missing or unevaluable data for non-target lesions. In this case, the overall assessment would 
be PR. 
 
Overall level of substantial worsening that merits discontinuation of therapy. A useful test that can be applied 
when assessing non-targets for unequivocal progression is to consider if the increase in overall disease burden 
based on the change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease. 
Stable Disease 
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 
 


 
 
 
Page | 51  
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 
review panel (or Principal Investigator). 
 
Unknown (UN): Assessment of non-target lesions cannot be made due to insufficient or unevaluable data. In 
this case, a concise explanation must be given. 
 
Evaluation of New Lesions 
 
Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something other than tumor (ex: new 
bone lesions may be healing or flare of pre-existing lesions). However, a lesion identified on a follow-up scan in 
an anatomical location that was not scanned at baseline is considered new and will indicate PD. If a new lesion 
is equivocal (because of small size, etc.), follow-up evaluation will clarify if it truly represents new disease and 
if PD is confirmed, progression should be declared using the date of the initial scan on which the lesion was 
discovered. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since 
the treatment started).  The patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 


 
 
 
Page | 52  
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time measurement criteria 
are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements recorded since 
the treatment started, or death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is objectively documented, or death due 
to any cause. Participants without events reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or registration) to death due 
to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from randomization (or 
registration) to the earlier of progression or death due to any cause. Participants alive without disease 
progression are censored at date of last disease evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from randomization (or registration) to 
progression, or censored at date of last disease evaluation for those without progression reported. 
 
11.1.7 Response Review 
 
All staging studies will be reviewed centrally by the Dana-Farber/Harvard Cancer Center Tumor Imaging 
Metrics Core (TIMC). 
 
11.1.8 Clinical Benefit 
 
Clinical benefit will be defined as confirmed CR plus confirmed PR plus stable disease of at least 24 weeks 
duration. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The QACT will collect, manage, and perform quality checks on the data for this study. 
 


 
 
 
Page | 53  
12.1.2 Responsibility for Data Submission 
 
Investigative sites are responsible for submitting data and/or data forms to the QACT according to the schedule 
set by the QACT. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual 
data from this study. The committee is composed of clinical specialists with experience in oncology and who 
have no direct relationship with the study. Information that raises any questions about participant safety will be 
addressed with the Overall PI and study team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review toxicity and 
accrual data. Information to be provided to the committee may include: up-to-date participant accrual; current 
dose level information; DLT information; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene 
therapy protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. scans, laboratory 
values) will be provided upon request.  
 
12.3 
Collaborative Agreements Language 
 
Not Applicable. 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a non-randomized, open-label, phase II study designed to evaluate the safety and efficacy of palbociclib, 
an oral selective CDK 4/6 inhibitor in combination with bazedoxifene, a third generation selective estrogen 
receptor modulator (SERM) in patients with metastatic hormone receptor positive breast cancer. Eligible 
participants must have histologically confirmed invasive breast cancer that is metastatic or unresectable locally 
advanced, and the breast cancer must be ER+/PR+, HER2- and endocrine resistant, and may have received up 
to  one prior line of chemotherapy for metastatic or unresectable locally advanced breast cancer. 
 
13.1 
Study Design/Endpoints 
 
 Primary endpoint: 
• Clinical benefit rate (CR + PR + SD ≥ 24 weeks)  
 
Secondary endpoints include: 
• Safety and toxicity profile  
• To evaluate objective response by RECIST 1.1.  
• Progression-free survival 
• Overall survival 
• Objective response, clinical benefit rate, progression free survival and overall survival for patients with 
ESR1 mutations. 
 
Statistical programming and analyses will be performed using SAS and other validated statistical software as 
required. 
 
 


 
 
 
Page | 54  
This study uses a Simon ‘optimal’ two-stage design, 17 patients will be enrolled in the first stage, and if the 
study continues to the second stage, another 20 patients would be enrolled.  A total of 37 patients will be 
enrolled in this study. If a dose de-escalation is performed, the patients that received the initial palbociclib dose, 
will not be evaluated for efficacy and the maximum number of patients in this study will be 43 patients.  
 
There are no phase I data with the combination of palbociclib and bazedoxifene. Based upon the observed 
toxicities to date, mechanism of action, and drug metabolism, no additive or synergistic toxicities are 
anticipated. Accrual will be paused and a formal monitoring of safety will be conducted when 6 patients have 
completed at least 1 cycle of treatment to determine if any toxicities requiring a dose de-escalation is needed. If 
>1 patient develops a dose limiting toxicity, a dose de-escalation to dose level -1 (100mg) will be performed 
and a formal monitoring of safety will be performed when 6 patients have completed at least 1 cycle of level -1 
dose. If >1 patient develops a dose limiting toxicity with level -1 dose, the study will be discontinued. The 
following table gives the probability of continuing after 6 patients under varying true rates of dose-limiting 
toxicity.   
 
 
 
Acceptable dosage using 6 subjects 
True DLT rate 
 0.1         0.2          0.3         0.4          0.5        0.6        0.7  
Probability  
 89%       66%       42%       23%       11%       4%        1% 
 
 
Accrual will be paused after the 17 patients are enrolled until at least 4 patients demonstrate clinical benefit at 6 
months (24 weeks) and all patients complete at least 2 cycles for safety evaluation. The length of the pause will 
range from 2 cycles to 6 months.  If 8 or more patients among the 17 patients enrolled in the first stage of the 
Phase II experience a DLT, the regimen will be considered too toxic and the study will be closed due to safety 
concern. . If 7 or less of 17 patients experience a DLT, continued enrollment to the second stage will be based 
on the Simon two-stage design to evaluate clinical benefit. Assuming that the true rate of adverse events is 30%, 
the probability that 8 or more patients experience DLT is 10%. Assuming an unacceptable adverse event rate of 
60%, there is a 91% probability of observing 8 or more events and stopping due to a safety concern.    
 
DLT is based on the CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE v4.0) and will be assessed over the first two cycles of treatment. A DLT will be defined as follows: 
 
• Grade 3 or higher hematologic or non-hematologic toxicity thought likely or definitely related to 
protocol therapy will be counted as a DLT, with the exception of: 
 
o Grade 3 neutropenia without fever 
o Grade 3 diarrhea that responds to maximal supportive measures. If grade 3 diarrhea is persistent > 7 
days despite maximal supportive measures, it will be counted as a DLT 
o Grade 3 fatigue 
o Grade 3 hot flashes 
o Grade 3 electrolyte disturbance, unless persistent > 7 days despite maximal supportive measure 
 
Patients who withdraw study consent before receiving any study treatment will be replaced. Patients who 
develop inevaluable disease during treatment or off study before follow-up disease evaluation would be 
considered as non-responders in final analyses.         
 


 
 
 
Page | 55  
13.2 
Sample Size, Accrual Rate and Study Duration 
 
A true clinical benefit rate of 20% or less would not be of clinical interest, and is the null hypothesis to the 
Simon two-stage design.   A true rate of 40% among patients with ER/PR+, HER2-, endocrine resistant 
metastatic or unresectable locally advanced breast cancer would be considered a clinically meaningful level of 
response, so the sample size was chosen to have high power (90%) to declare the combination effective at this 
rate, while controlling the one-sided Type I error at no more than 10% under the null.  
 
Using the Simons optimal method, in the first stage, 17 patients will be enrolled. If there are at least 4 
responses, accrual will continue to the second stage where up to 20 additional patients will be enrolled. If at 
least 11 of these 37 patients have response (≥30%), the regimen will be considered worthy of further 
study.  With this design, the probability of stopping the trial early is 55% if the true response rate is 20%. If the 
true response rate is 40% the chance that the regimen is declared worthy of further study is 90%. 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
3 
+ 
0 
= 
3 
Not Hispanic or Latino 
34 
+ 
0 
= 
34 
Ethnic Category: Total of all subjects 
37 
+ 
0 
= 
37 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
3 
+ 
0 
= 
4 
Black or African American 
3 
+ 
0 
= 
4 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
31 
+ 
0 
= 
31 
Racial Category: Total of all subjects 
37 
+ 
0 
= 
37 
 
 
 
 
 
 
 
13.3 
Analysis of Primary Endpoints 
 
The primary endpoint is clinical benefit at 24 weeks. Patients who received at least one dose of the study 
regimens will be included in the assessment of objective response. Assuming the study does not terminate early 
and all patients enrolled begin protocol therapy, the 95% CI for the response rate will be determined accounting 
for the two-stage design.  
 
13.4 
Analysis of Secondary Endpoints 
 
All patients who receive at least one dose of the study regimens will be included in the assessment of safety and 
toxicity.  
 


 
 
 
Page | 56  
Adverse event information will be collected from the time the subject signs the ICF until resolution or for 30 days 
after the subject’s last study visit, whichever comes first. Treatment-emergent AEs (TEAEs) will be analyzed. 
Adverse events will be regarded as TEAEs if they started on or after the date and time of administration of the 
first dose of study treatment or if they were present before the administration of the first dose of study treatment 
and increased in severity during the study. Treatment-emergent peripheral neuropathy will be followed until 
resolution or until the start of another anticancer therapy post treatment, whichever occurs first.  
Adverse events will be graded using CTCAE v 4.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).   Investigators will collect all CTCAE grades 
for all AEs (to assess both increasing and decreasing severity). Events will be summarized by frequency and 
percentage by grade and by type. 
The incidence of TEAEs and relatedness to study treatment will be summarized.  
Objective response rate will be calculated and the 95% CI for the response rate will be determined accounting 
for the two-stage design.   
 
Progression-free survival and Overall survival, as defined in section 11.1.6, will be described using the method 
of Kaplan-Meier.  The point estimate of median PFS and OS, as well as estimates of PFS and OS at other time 
points, will be presented with 95% confidence intervals. 
    
It is anticipated that 20% of patients will have detectable ESR1 mutations. Assuming a 40% clinical benefit rate 
and a 20% ESR1 mutation rate, we have 80% power to detect the difference of clinical benefit rates between 
patients with and without ESR1 mutation if the clinical benefit rate is 80% among patients with ESR1 mutation 
and 30% among patients without ESR1 mutation. The following table gives the power of detecting the clinical 
benefit rate difference among patients with and without ESR1 mutation, assuming the total sample size is 37 
and clinical benefit rate is 40%. 
 
ESR1 
mutation rate 
# of pts with 
ESR1 
mutation 
# of pts 
without ESR1 
mutation 
CBR among 
pts with ESR1 
mutation 
CBR among pts 
without ESR1 
mutation 
Power 
20% 
7 
30 
80% 
30% 
82% 
7 
30 
75% 
33% 
70% 
7 
30 
70% 
31% 
57% 
25% 
9 
28 
80% 
27% 
92% 
9 
28 
75% 
28% 
82% 
9 
28 
70% 
30% 
69% 
30% 
11 
26 
80% 
23% 
97% 
11 
26 
75% 
25% 
91% 
11 
26 
70% 
27% 
80% 
   
 
Other analyses for correlative objectives are exploratory with no plans for formal hypothesis testing given the 
limited sample size. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All participants who have received at least one dose of study regimens will be evaluable for toxicity.  
 


 
 
 
Page | 57  
13.5.2 Evaluation of Response 
 
All participants who have received at least one dose of study regimens will be evaluable for response. 
Patients who develop inevaluable disease during treatment or off study before follow-up disease 
evaluation would be considered as non-responders in final analyses.     
   
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of the study is the 
time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for 
analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be 
published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of 
the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no 
later than three (3) years after the end of the study.  
 
 


 
 
 
Page | 58  
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Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. 
Genes & development 1999, 13(12):1501-1512. 
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van den Heuvel S, Harlow E: Distinct roles for cyclin-dependent kinases in cell cycle control. 
Science 1993, 262(5142):2050-2054. 
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Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 1995, 81(3):323-330. 
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Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ: The p21 Cdk-interacting protein Cip1 is a 
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Koff A, Ohtsuki M, Polyak K, Roberts JM, Massague J: Negative regulation of G1 in mammalian 
cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science 1993, 260(5107):536-539. 
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Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A: p27Kip1, a cyclin-Cdk 
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Butt AJ, McNeil CM, Musgrove EA, Sutherland RL: Downstream targets of growth factor and 
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F, Weisz A: Estrogen induces early and timed activation of cyclin-dependent kinases 4, 5, and 6 
and increases cyclin messenger ribonucleic acid expression in rat uterus. Endocrinology 1997, 
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Geum D, Sun W, Paik SK, Lee CC, Kim K: Estrogen-induced cyclin D1 and D3 gene expressions 
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Watts CK, Brady A, Sarcevic B, deFazio A, Musgrove EA, Sutherland RL: Antiestrogen inhibition of 
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Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, Yang G, Chalukya M, Wang HJ, 
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19. 
Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, 
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Peano BJ, Crabtree JS, Komm BS, Winneker RC, Harris HA: Effects of various selective estrogen 
receptor modulators with or without conjugated estrogens on mouse mammary gland. 
Endocrinology 2009, 150(4):1897-1903. 
25. 
Lewis-Wambi JS, Kim H, Curpan R, Grigg R, Sarker MA, Jordan VC: The selective estrogen receptor 
modulator bazedoxifene inhibits hormone-independent breast cancer cell growth and down-
regulates estrogen receptor alpha and cyclin D1. Molecular pharmacology 2011, 80(4):610-620. 
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Wardell SE, Nelson ER, Chao CA, McDonnell DP: Bazedoxifene exhibits antiestrogenic activity in 
animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced 
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27. 
Ronkin S, Northington R, Baracat E, Nunes MG, Archer DF, Constantine G, Pickar JH: Endometrial 
effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal 
women. Obstetrics and gynecology 2005, 105(6):1397-1404. 
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Miller PD, Chines AA, Christiansen C, Hoeck HC, Kendler DL, Lewiecki EM, Woodson G, Levine AB, 
Constantine G, Delmas PD: Effects of bazedoxifene on BMD and bone turnover in postmenopausal 
women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. Journal 
of bone and mineral research : the official journal of the American Society for Bone and Mineral 
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29. 
Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, Constantine GD, 
Chines AA: Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal 
women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled 
clinical trial. Journal of bone and mineral research : the official journal of the American Society for 
Bone and Mineral Research 2008, 23(12):1923-1934. 
30. 
Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, 
Gralow JR, Livingston RB et al: Combination anastrozole and fulvestrant in metastatic breast 
cancer. The New England journal of medicine 2012, 367(5):435-444. 
31. 
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, 
Smirnova I, Lichinitser MR et al: Results of the CONFIRM phase III trial comparing fulvestrant 
250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive 
advanced breast cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2010, 28(30):4594-4600. 
32. 
Robertson JF, Nicholson RI, Bundred NJ, Anderson E, Rayter Z, Dowsett M, Fox JN, Gee JM, Webster 


 
 
 
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A, Wakeling AE et al: Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-
pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen 
in postmenopausal women with primary breast cancer. Cancer research 2001, 61(18):6739-6746. 
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Oxnard GR, Paweletz CP, Kuang Y, Mach SL, O'Connell A, Messineo MM, Luke JJ, Butaney M, 
Kirschmeier P, Jackman DM et al: Noninvasive detection of response and resistance in EGFR-
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Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT: Bone imaging in metastatic 
breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2004, 22(14):2942-2953. 
 
 
 


 
 
 
Page | 61  
APPENDIX A  ECOG PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, 
but unable to carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 


 
 
 
Page | 62  
APPENDIX B  LIST OF DRUGS KNOWN TO PREDISPOSE TO TORSADE DE POINTES 
 
Generic Name  
Brand Name 
Amiodarone 
Arsenic trioxide 
Astemizole 
Azithromycin 
Bepridil 
Chloroquine 
Chlorpromazine 
Cisapride 
Citalopram 
Clarithromycin 
Disopyramide 
Dofetilide 
Domperidone 
Droperidol 
Erythromycin 
Flecainide 
Halofantrine 
Haloperidol 
Ibutilide 
Levomethadyl 
Mesoridazine 
Methadone 
Moxifloxacin 
Pentamidine 
Pimozide 
Probucol 
Procainamide 
Quinidine 
Sotalol 
Sparfloxacin 
Terfenadine 
Thioridazine 
Vandetanib 
Cordarone®, Pacerone®  
Trisenox®  
Hismanal®  
Zithromax®  
V ascor®  
Aralen®  
Thorazine®  
Propulsid®  
Celexa®  
Biaxin®  
Norpace®  
Tikosyn®  
Motilium®  
Inapsine®  
Erythrocin®, E.E.S.® 
Tambocor®  
Halfan®  
Haldol®  
Corvert®  
Orlaam®  
Serentil®  
Dolophine®, Methadose®  
Avelox®  
Pentam®, NebuPent®  
Orap®  
Lorelco®  
Pronestyl®, Procan® 
Cardioquin®, Quinaglute® 
Betapace®  
Zagam®  
Seldane®  
Mellaril®  
Caprelsa® 
 
 
 


 
 
 
Page | 63  
APPENDIX C  CYP3A INDUCERS/INHIBITORS AND INFORMATION ON POSSIBLE DRUG 
INTERACTIONS 
 
Medications that strongly inhibit CYP3A: 
Amprenavir  
Atazanavir  
Boceprevir  
Clarithromycin  
Conivaptan  
Delavirdine  
Diltiazem  
Erythromycin  
Fosamprenavir  
Indinavir  
Itraconazole  
Ketoconazole  
Lopinavir  
Mibefradil  
Miconazole  
Nefazodone  
Nelfinavir  
Posaconazole  
Ritonavir  
Saquinavir  
Telaprevir  
Telithromycin  
Verapamil 
Voriconazole  
Grapefruit, grapefruit juice, or any product containing grapefruit 
 
Medications that strongly induce CYP3A: 
Carbamazepine  
Felbamate  
Nevirapine  
 
Phenytoin  
Primidone  
Rifabutin 
Rifampicin  
Rifampin  
Rifapentin 
St. John’s wort 
 
Medications that moderately induce CYP3A: 
Bosentan 
Efavirenz 
Etravine 
Modafinil 
Nafcillin 
 


 
 
 
Page | 64  
APPENDIX D  STUDY PARTICIPANT SELF-ADMINISTERED DRUG DIARY 
 
PATIENT INSTRUCTIONS:  
Take your medications exactly as prescribed by your doctor.  See the next pages for specific doses for each 
medication that you are taking on this study.  
For Palbociclib:  
• Keep Palbociclib capsules in the bottle(s) provided and do not transfer them to any other container. 
Store at room temperature. 
• Palbociclib should be taken by mouth once per day. Palbociclib should be taken with food.  
Grapefruit, grapefruit juice or anything that contains grapefruit juice and St. John’s wort must be 
avoided while on study.  
• Capsules must be swallowed whole. Do not soak capsules or empty contents into any food or drink.  
• If you vomit after taking Palbociclib, do NOT take another dose. Please note any vomiting in the 
Comments section of the diary on the next page.  
• If a dose is missed and it is less than 6 hours from usual time of dosing, then you may take that dose. 
Otherwise that dose should be skipped and NOT taken. You should resume regular dosing the 
following day.  If you miss a dose, record “0” for Number Taken on the next page.  
• If you accidentally take an extra dose during a day skip the next day’s dose and record the extra dose 
on the next page.   
For Bazedoxifene:  
• Keep Bazedoxifene tablets in the blister card(s)provided and do not transfer them to any other container. 
Store at room temperature. 
• Bazedoxifene should be taken by mouth once per day. Bazedoxifene can be taken with or without 
food. 
• If you vomit after taking Bazedoxifene, do NOT take another dose. Please note any vomiting in the 
Comments section of the diary on the next page.  
• If a dose is missed and it is less than 6 hours from usual time of dosing, then you may take that dose. 
Otherwise that dose should be skipped and NOT taken. You should resume regular dosing the 
following day.  If you miss a dose, record “0” for Number Taken on the next page.  
• If you accidentally take an extra dose during a day skip the next day’s dose and record the extra dose 
on the next page.  
    FOR CLINIC USE ONLY: 
Give patient all 3 pages of Drug Diary stapled 
together. Provide one diary per cycle (28 days). 
 
Complete patient identifiers and medical team 
contact information on pages 2 and 3. 
 
Complete correct dose levels for Palbociclib and 
Bazedoxifene treatment on page 2. 
 
When patient returns pill bottles/blister cards and 
diary perform a Palbociclib and Bazedoxifene 
pill count and record adherence information in 
the box to the right. 
Staff Initials: 
Date Dispensed: 
 
Date Returned: 
# Palbociclib capsules 
dispensed: 
# Palbociclib capsules 
returned: 
# Palbociclib capsules that should have been 
taken: 
# Bazedoxifene tablets 
dispensed 
# Bazedoxifene tablets 
returned: 
# Bazedoxifene tablets that should have been 
taken: 
Discrepancy Notes: 


 
 
 
Page | 65  
15-060 STUDY PARTICIPANT SELF-ADMINISTERED DIARY  
 
Participant Name: ___________________________________                         Cycle #: ______ 
Your Doctor: ____________________________    Phone: ____________________ 
 
Your Nurse: _____________________________   Phone: ____________________ 
 
PALBOCICLIB 
STUDY DRUG INSTRUCTIONS: Take one Palbociclib capsule on Days 1 – 21. Record the dose of each 
medication on the chart to the right after taking each day. 
 
Date 
Time 
Number of 
Palbociclib 
Capsules Taken 
Comments 
Ex: 
6/1/2009 
      8 : 15     AM   
 PM 
1 
Vomited 1 hour later 
Day 1 
  
         :          AM   
 PM 
  
  
Day 2 
  
         :          AM   
 PM 
  
  
Day 3 
  
         :          AM   
 PM 
  
  
Day 4 
  
         :          AM   
 PM 
  
  
Day 5 
  
         :          AM   
 PM 
  
  
Day 6 
  
         :          AM   
 PM 
  
  
Day 7 
  
         :          AM   
 PM 
  
  
Day 8 
  
         :          AM   
 PM 
  
  
Day 9 
  
         :          AM   
 PM 
  
  
Day 10 
  
         :          AM   
 PM 
  
  
Day 11 
  
         :          AM   
 PM 
  
  
Day 12 
  
         :          AM   
 PM 
  
  
Day 13 
  
         :          AM   
 PM 
  
  
Day 14 
  
         :          AM   
 PM 
  
  
Day 15 
  
         :          AM   
 PM 
  
  
Day 16 
  
         :          AM   
 PM 
  
  
Day 17 
  
         :          AM   
 PM 
  
  
Day 18 
  
         :          AM   
 PM 
  
  
Day 19 
  
         :          AM   
 PM 
  
  
Day 20 
  
         :          AM   
 PM 
  
  
Day 21 
  
         :          AM   
 PM 
  
  
 
Do not take any Palbociclib after: _____/_____/_________   
 
 
Patient Signature: _______________________________________   Date: _____/_____/_________ 
 
 
 


 
 
 
Page | 66  
15-060 STUDY PARTICIPANT SELF-ADMINISTERED DIARY  
 
Participant Name: ___________________________________                         Cycle #: ______ 
BAZEDOXIFENE 
STUDY DRUG INSTRUCTIONS: Take two Bazedoxifene 20mg tablets on Days 1 – 28. Record the dose of 
each medication on the chart to the right after taking each day. 
Date 
Time 
Number of Pills 
Taken 
Comments 
Ex: 
6/1/2009 
      8 : 15     AM   
 PM 
1 
Vomited 1 hour later 
Day 1 
  
         :          AM   
 PM 
  
  
Day 2 
  
         :          AM   
 PM 
  
  
Day 3 
  
         :          AM   
 PM 
  
  
Day 4 
  
         :          AM   
 PM 
  
  
Day 5 
  
         :          AM   
 PM 
  
  
Day 6 
  
         :          AM   
 PM 
  
  
Day 7 
  
         :          AM   
 PM 
  
  
Day 8 
  
         :          AM   
 PM 
  
  
Day 9 
  
         :          AM   
 PM 
  
  
Day 10 
  
         :          AM   
 PM 
  
  
Day 11 
  
         :          AM   
 PM 
  
  
Day 12 
  
         :          AM   
 PM 
  
  
Day 13 
  
         :          AM   
 PM 
  
  
Day 14 
  
         :          AM   
 PM 
  
  
Day 15 
  
         :          AM   
 PM 
  
  
Day 16 
  
         :          AM   
 PM 
  
  
Day 17 
  
         :          AM   
 PM 
  
  
Day 18 
  
         :          AM   
 PM 
  
  
Day 19 
  
         :          AM   
 PM 
  
  
Day 20 
  
         :          AM   
 PM 
  
  
Day 21 
  
         :          AM   
 PM 
  
  
Day 22 
         :          AM   
 PM 
Day 23 
         :          AM   
 PM 
Day 24 
         :          AM   
 PM 
Day 25 
         :          AM   
 PM 
Day 26 
         :          AM   
 PM 
Day 27 
         :          AM   
 PM 
Day 28 
         :          AM   
 PM 
 
 
Patient Signature: _______________________________________   Date: _____/_____/________ 
 


 
 
 
Page | 67  
APPENDIX E  RESEARCH SPECIMEN COLLECTION/SHIPPING GUIDELINES 
 
 
Research Biopsy Guidelines 
 
Tissue specimens will be collected from recurrent or metastatic lesions using standard institutional procedures. 
The amount of tissue collected will follow the guidelines listed below: 
 
• Breast: A goal of 3-6 core biopsy specimens will be obtained using standard institutional guidelines for 
a diagnostic core biopsy of a breast mass. 
 
• Skin/chest wall: A goal of 1-2 5-mm punch biopsies will be obtained. 
 
• Lymph node: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle. 
 
• Liver: A goal of 3-6 core biopsy specimens will be obtained using an 18-gauge needle. 
 
• Lung: Because of the risk of pneumothorax associated with core needle biopsies of lung nodules, no 
core biopsies of lung nodules will be performed on this protocol; unless if they are clinically indicated.  
 
• Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively low, if a patient 
has another accessible site of disease (i.e. skin, lymph node, liver), that site should be biopsied 
preferentially. If bone is the only biopsy-accessible site, then a goal of 3-6 core biopsy specimens will be 
obtained using an 11-13 gauge needle. 
 
• Pleural Fluid: A goal of 500 cc of pleural fluid will be obtained with a standard thoracentesis procedure, 
with or without image guidance, according to the clinical judgment of the treating physician and 
clinician performing the procedure. Less than the goal amount is acceptable, and should be based upon 
the clinical judgment of the Investigator and the clinician performing the procedure. If more than the 
goal amount of fluid is obtained, then the entire specimen (with the exception of what is needed for 
clinical purposes, if applicable) will be stored in the tissue bank. 
 
• Ascites fluid:  A goal of 500 cc of ascites fluid will be obtained with a standard paracentesis procedure, 
with or without image guidance, according to the clinical judgment of the treating physician and 
clinician performing the procedure. Less than the goal amount is acceptable, and should be based upon 
the clinical judgment of the Investigator and the clinician performing the procedure. If more than the 
goal amount of fluid is obtained, then the entire specimen (with the exception of what is needed for 
clinical purposes, if applicable) will be stored in the tissue bank. 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Page | 68  
Please note that the above are guidelines for the amount of tissue to be obtained, and are not meant to 
replace clinical judgment at the time the procedure is performed. Less than the goal quantity of tissue is 
accepted for each type of biopsy, and will be left to the clinical judgment of the physician performing the 
procedure. If ascites or pleural fluid is to be used as the investigational biopsy specimen, consideration should 
be given to confirming the malignant nature of the ascites or pleural fluid prior to study entry. 
 
If a patient is undergoing resection of a lesion for clinical reasons (i.e. wedge resection of a new lung lesion 
for confirmation of diagnosis or re-testing of hormone receptor or HER2 status; or, resection of a chest wall 
lesion; or, resection of a lymph node), then the patient may opt to have a portion of that tissue (roughly 
equivalent to the goal amount of tissue listed in the guidelines above, i.e. the equivalent of two 5-mm punch 
biopsies of the skin, or 3-6 18-gauge core biopsies) stored for research at the time of the procedure (provided 
that the tissue is processed as specified in Section 8.3 ), in which case, the patient would not be required to 
undergo a separate research biopsy for entry into this protocol. 
 
Tissue Biopsy Handling and Processing 
 
Following research biopsy of a specimen, 1 tissue core will be placed in formalin and sent to SHL for 
embedding in paraffin. FFPE blocks will be sectioned and 20 slides will be cut for H+E and 
Immunohistochemistry staining that will be performed at the SHL core directed by Dr. Jon Aster.  The other 
cores will be frozen in OCT and sent to the Broad Institute for the Center for Cancer Precision Medicine 
(CCPM) testing (whole exome sequencing and RNAseq). The remaining tissue will be stored for future 
research. All samples will be anonymized by assigning a unique sample ID number prior to use.  
 
Archival Tissue Collection 
 
Tissue blocks of primary and/or metastatic tumor samples should be sent to Dana- Farber Cancer Institute 
within in 2 weeks of the start of protocol therapy. If blocks cannot be submitted, 20 unstained slides are 
acceptable.   
 
Cell free DNA (cfDNA) blood collection 
 
Blood will be collected at baseline and on Day 1 of each cycle. One 10 ml of blood will be collected in EDTA 
containing tube at each time point. The samples will be sent to the DFCI breast blood bank and processed for 
cell free plasma. Samples will be sent to the Broad Institute for low passage sequencing to assess cell free DNA 
and samples that are found to have adequate tumor DNA will undergo whole exome sequencing. Analysis of the 
ESR1 mutations using droplet-digital PCR will also be performed at the Belfer Institute, DFCI.  
 
Broad Institute 
Contact: Megan Hana 
Manager of Operations Cancer Center Genome Analysis 
75 Ames St.  
Cambridge, MA 02142 
 
Belfer Institute  
Contact: Cloud Paweletz Ph.D. 
Harvard Institutes of Medicine 
4 Blackfan St. 
Boston, MA 02215 
 


 
 
 
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Germline DNA blood collection 
One 10 ml EDTA tube will be collected for research at baseline and will be sent to the Broad Institute for the 
Center for Cancer Precision Medicine (CCPM) testing for germline DNA testing.  If for any reason this sample 
is not collected at baseline, it can be collected at another time point during the study.  Excess germline DNA 
will be returned to DF/HCC Clinical Trials Core laboratory. 
 
 
APPENDIX F  INVESTIGATOR-INITIATED RESEARCH DRUG SUPPLY REQUEST 
 


 
 
 
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APPENDIX G  PHARMACY RECOMMENDATIONS FOR DISPENSING PALBOCICLIB 
 
For this trial Pfizer distributes Palbociclib in bottles containing 23 capsules.  Participants should only take 21 
capsules (Days 1-21 of each 28 day cycle).  With approval from Pfizer and as a preventive measure and from 
participants taking all 23 capsules we are recommending that pharmacies remove the 2 extra capsules from each 
bottle before dispensing to the participants since Pfizer is unable to distribute bottles containing only 21 
capsules.  While this is not required we strongly recommend this procedure to prevent participants from taking 
extra capsules. 
 
This process will require careful drug account ability documentation.  On the DARF document that 21 capsules 
were dispensed to the participant.  A second line should be recorded to state “Destroyed per SOP” in the patient 
initials and MRN fields and “-2” for the amount dispensed.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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APPENDIX H  REPORTABLE EVENT FAX COVER SHEET FOR REPORTING TO PFIZER