Clinical trial NCT02871791
Conditions: Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Hormone Receptor (HR)-Positive Breast Cancer
Keywords: Her2-negative metastatic breast cancer Hormone receptor (HR)-positive breast cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-08-24; Completion date: 2021-09-01
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a combination of targeted therapy and hormonal therapy as a possible treatment for breast cancer that has spread to other places in the body and is hormone receptor positive (HR+) and HER2-negative.

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

* Palbociclib
* Everolimus
* Exemestane

Detailed description:
This is a Phase I/II clinical trial. The Phase I portion of this clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. The Phase II portion of the study 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.

The FDA (the U.S. Food and Drug Administration) has not approved the combination of Palbociclib, Everolimus, and Exemestane as a treatment for any disease.

This is the first time that the combination of Palbociclib, Everolimus, and Exemestane will be given to humans.

Palbociclib is a drug that may stop cancer cells from growing. Palbociclib blocks activity of two closely related enzymes (proteins that help chemical reactions occur in the body), 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 regulate cell growth. Laboratory testing has suggested Palbociclib may stop the growth of HR+ breast cancer.

Everolimus is a type of drug called an mTORinhibitor that treats breast cancer by preventing the cells from multiplying by inhibiting the pathway, or a sequence of steps, known to regulate cell reproduction. Everolimus also may stop the growth of cancer cells by decreasing blood supply to the cancer cells.

Exemestane is an anti-hormone therapy that prevents breast cancer cell growth by blocking estrogen receptor stimulation. Premenopausal women will also receive an injection drug called an LHRH (luteinizing hormone-releasing hormone) agonist to shut down ovary function. It is standard of care for people with breast cancer, specifically with HR+ breast cancer, to take anti-hormone therapy.

The combination of everolimus and exemestane is FDA approved to treat this type of breast cancer.

The purpose of the Phase I portion of this research study is to determine a safe and tolerable dose of the combination of Palbociclib, Everolimus, and Exemestane for participants with ER-positive, HER2-negative advanced breast cancer.

The purpose of the Phase II portion of this research study is to determine whether the combination of Palbociclib, Everolimus, and Exemestane is an effective treatment for participants with ER-positive, HER2-negative advanced breast cancer.

Arms: arm 1: * Palbociclib will be administered orally, 100mg, once daily for 21 consecutive days followed by a 7-day rest (28-day cycle)
* Everolimus will be administered orally, 5mg, once daily on a 28 day schedule
* Exemestane will be administered orally, 25mg, once daily on a 28 day schedule
Interventions: intervention 1: Palbociclib intervention 2: Everolimus intervention 3: Exemestane
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 2 
Date Submitted: 07/23/2018 
Alert Page 
DF/HCC Protocol #: 16-177 
 
Revised: 01.08.16 
 
 
Dose Escalation Table  
 
Effective Date 
Dose Level / Cohort # 
Dose (insert units) 
Closed 
Dose 0 
100mg Palbociclib 
5mg Everolimus 
25mg Exemestane 
Closed 
Dose 1 
125mg Palbociclib 
5mg Everolimus 
25mg Exemestane 
 
Dose Expansion Table 
 
Effective Date 
Dose Level / Cohort # 
Dose (insert units) 
3/22/17 
Phase 2A 
100mg Palbociclib 
5mg Everolimus 
25mg Exemestane 
 
 
Note: The row for the current dose level is highlighted and bolded. 
 
 
Protocol Clarifications (non-drug related e.g. eligibility criteria, study 
assessments) 
 
 
Important note regarding restaging tumor assessments: 
 
There is an error in the Study Calendar, footnote F. This Alert Page serves to 
clarify that after C6 scans, restaging tumor assessments should be 
performed at the end of every 3 cycles (i.e. end of C9, C12, C15)—not every 
4 cycles. This correction will be included in an upcoming amendment. 
 
 
Safety / Drug (includes preparation, administration, dose modifications, 
equations) 
 
Important note regarding platelet counts: 


Page 2 of 2 
Date Submitted: 07/23/2018 
Alert Page 
DF/HCC Protocol #: 16-177 
 
Revised: 01.08.16 
 
There is a discrepancy between Protocol, Section 5.6.2 – Cycle 1, Day 1 and 
subsequent cycles, in which the treatment criteria states platelets should be > 
100,000/mm3 and Table 6-4, which states platelet counts should be 75 x 109/L 
(or > 75,000/mm3) to resume treatment. 
 
This Alert Page serves to clarify that patients can continue treatment with 
all three study medications if their platelet counts fall between 75,000/mm3 
and 100,000/mm3 at Day 1 for all cycles after C1D1. This correction will be 
included in an upcoming amendment. 
 
 


 
 
 
 
 
 
 
Office for Human Research Studies 
 
DANA-FARBER / HARVARD CANCER CENTER 
Version: 05.15.2017 
 
 
Protocol Front Sheet 
DFCI Protocol No.: 16-177  
 
1.  PROTOCOL INFORMATION 
 
Title: A Phase 1b/2a Study Of Palbociclib In Combination With Everolimus And Exemestane In Postmenopausal Women With Estrogen Receptor 
Positive and HER2 Negative Metastatic Breast Cancer 
Phase: Phase 1/2 
Sponsor Study Number:       
 
2.  DF/HCC STUDY CONTACT INFORMATION 
 
Primary Study Contact: Rebecca Rees  
Email:  Rebecca_Rees@dfci.harvard.edu 
Phone:  617.582.9478 
 
INVESTIGATORS:  (List only those under DFCI IRB, i.e., from institutions listed in Section 6 below) 
Overall PI: 
Sara Tolaney, MD MPH 
Phone: 617-632-3800 
Institution(s): DFCI 
Mgmt group: 
Breast Oncology 
Site Responsible PI: Neelam Desai, MD 
Nikhil Wagle, MD 
Phone: 617-632-8646 
617.632.3800 
Institution(s): BIDMC 
Broad 
Institute 
Mgmt group: 
Breast Oncology 
Breast Oncology 
 
 
3.  DRUG / DEVICE INFORMATION    N/A: 
  
 
 Drug(s), Biologic(s):  Palbociclib, Exemestane, Everolimus 
 Device(s) Name:        
Provided by: Palbociclib provided by Pfizer 
IND Exempt: 
        ‐or‐ 
IND#:            Holder Type: [pull down]    
IND Holder Name:        
Provided by:      
IDE Exempt: 
        ‐or‐ 
IDE #:            Holder Type: [pull down]    
IDE Holder Name:        
 
4.  PROTOCOL COORDINATION, FUNDING, MODE 
 
Regulatory Sponsor: 
Funding/Support (check all that apply): 
DF/HCC Investigator  Sara Tolaney, MD MPH 
 Industry: Pfizer 
 
 
 Federal Organization:       
 
CTEP Study: No 
      Grant #:       
 
 
 Internal Funding:       
 
 
 Non-Federal:       
 
 Other:       
 
Protocol Involves (check all that apply as listed in the protocol document, even if not part of the research but is mandated by the protocol document): 
 Chemotherapy 
 Hormone Therapy 
 Medical Record Review 
 Immunotherapy 
 Vaccine 
 Questionnaires/Surveys/Interviews 
 Surgery 
 Engineered Cell Therapy (ECT) 
 Data Repository 
 Radiological Exams 
 Bone Marrow/Stem Cell Transplant 
 Exercise/Physical Therapy 
 Required Biopsy Study 
 Cell Based Therapy 
 Genetic Studies 
 Human Embryonic Stem Cell 
 Gene Transfer (use of recombinant DNA or 
synthetic nucleic acid molecules) 
 Human Material Banking 
 Quality of Life 
 
 Radiation Therapy 
 Human Material Collection 
 Other:       
 
5.  SUBJECT POPULATION (also applies to medical record review and specimen collection studies) 
 
Total Study-Wide Enrollment Goal: 50 
Greater than 25% of the overall study accrual will be at DF/HCC: 
 Yes   
 No 
Total DF/HCC Estimated Enrollment Goal: 50 
Adult Age Range: 18+ 
Pediatric Age Range:       
Will all subjects be recruited from pediatric clinics?    
 Yes    
 No 
If enrolling both adults and pediatric subjects, anticipated percent of pediatric subjects:       
Retrospective Medical Record Reviews only (Please provide date range): from       to       
 
6.  SITES UNDER DFCI IRB (check all that apply) 
 
DF/HCC Main Sites: 
DF/HCC Satellite Sites: 
 Beth Israel Deaconess Medical Center (BIDMC) 
 Beth Israel Deaconess Medical Center – Needham (BIDMC-Needham) 
 Boston Children’s Hospital (BCH) 
 Dana-Farber/New Hampshire Oncology-Hematology (DFCI @ NHOH) 
 Brigham and Women’s Hospital (BWH) 
 Dana-Farber at Steward St. Elizabeth’s Medical Center (DFCI @ SEMC) 
 Dana-Farber Cancer Institute (DFCI) 
 Dana-Farber at Milford Regional Cancer Center (DFCI @ MRCC) 
 Massachusetts General Hospital (MGH) 
 Mass General/North Shore Cancer Center (MGH @ NSCC) 
 
 Mass General at Emerson Hospital – Bethke (MGH @ EH) 
 
 Mass General at Newton-Wellesley Hospital (MGH @ NWH) 
DF/PCC Affiliate Sites: 
 DF/BWCC in Clinical Affiliation with South Shore Hospital (DFCI @ SS) 
  Cape Cod Healthcare (CCH)  
 Brigham and Women’s Hospital at Faulkner Hospital (BWH @ FH) 
  Lowell General Hospital (LGH) 
  New England Cancer Specialists (NECS)  
 
 
 
 
 
 
 
 Broad Institute 
  
 
 
 
              
 


Protocol Front Sheet 
 
FS Page: 2 
 
Harvard Catalyst Member(s): (list institution/location) 
 
                                                                 
 
 
 
                 
 
 
 
 
                  
 
 
7.  DF/HCC INITIATED STUDIES ONLY  - SITES UNDER OTHER IRB  (N/A: 
) 
 
 
DF/HCC Multi-Center Sites: (list institution/location) 
      
      
 
 
 
  Multicenter Site(s) with Master CTA: (list institution/location) 
         
         
  
      
 
 
         


Log Sheet 
Page 1 of 1 
 
Protocol Number: 16-177 
 
Approval Date:    06/21/16 (IRB meeting date when protocol/consent  
 approved or conditionally approved) 
 
Activation Date:    08/24/16 (Date when protocol open to patient entry) 
 
Approval signatures are on file in the Office for Human Research Studies, tel. 617-632-3029. 
 
Date 
Posted 
Revised Sections 
IRB Approval 
Date 
OnCore 
Version Date 
08/24/16 
Protocol, Eligibility Checklist and Front Sheet revised 
due to Amendment #1 
07/28/16 
08/24/16 
Date 
Posted 
 
Revised Sections 
Approved 
Date 
Version Date 
(OnCore) 
01/13/17 
Eligibility checklist and Protocol replaced due to 
Amendment # 2 
11/15/16 
N/A 
02/06/17 
Alert Page and Eligibility Checklist replaced due 
Amendment #3 
01/25/17 
N/A 
04/18/17 
Protocol and Eligibility Checklist replaced due to 
Amendment #4 
03/23/17 
N/A 
05/16/17 
Consent Form replaced due to Amendment #6 
05/03/2017 
05/16/2017 
05/16/17 
Delay Activation Status Page added: BIDMC site added 
but not active:  Front Sheet, Alert Page, and Eligibility 
Checklist and Consent Form replaced due to 
Amendment #5 (note: DFCI active 08/24/16) 
05/09/2017 
05/16/2017 
05/24/17 
Correction AM# 4: Protocol replaced (administrative 
revision) 
N/A 
N/A 
05/30/17 
Study renewal/ Consent form footer replaced due to 
Continuing Review #1 
05/18/17 
05/26/17 
06/28/17 
Consent Form replaced due to Amendment #7 
05/22/2017 
06/07/2017 
07/07/17 
Delayed Activation Status Page from AM#5 removed: 
BIDMC ready for activation 
N/A 
N/A 
08/10/17 
Front Sheet, Protocol and Consent Form replaced due 
to Amendment #8 
07/21/2017 
08/01/2017 
08/10/17 
Protocol and Eligibility Checklist replaced due to 
Amendment #9 
07/03/17 
n/a 
08/10/17 
Protocol and Eligibility Checklist replaced due to 
Amendment #10 
07/27/17 
n/a 
12/13/2017 
Protocol, Eligibility Checklist replaced per Amendment 
#11 
11/07/2017 
n/a 
04/12/2018 
Study renewal/Consent Form footer replaced per 
Continuing Review #2 
04/03/2018 
04/10/2018 
05/17/2018 
Alert Page replaced per Amendment #12 
04/30/2018 
n/a 
08/23/2018 
Alert Page replaced per Amendment #13 
07/27/2018 
n/a 
02/28/2019 
Study renewal/Consent Form footer replaced per 
Continuing Review #3 
02/28/2019 
02/28/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


1 
 
NCI Protocol #: 
N/A. 
 
DF/HCC Protocol #: 16-177 
 
 
TITLE:  A Phase 1b/2a Study Of Palbociclib In Combination With Everolimus And Exemestane 
In Postmenopausal Women With Estrogen Receptor Positive and HER2 Negative Metastatic 
Breast Cancer. 
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
*Principal Investigator (PI): 
Sara Tolaney, MD MPH 
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave. (CLS 11059) Boston, MA 02215
 
Telephone – 617-632-5743 
 
Fax – 617-632-1930 
 
Sara_Tolaney@dfci.harvard.edu  
 
Other Investigators: 
Arlindo R. Ferreira, MD MSc 
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave. (CLS 11059) Boston, MA 02215 
 
 
ArlindoR_Ferreira@dfci.harvard.edu  
 
 
Nikhil Wagle, MD 
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave. (CLS 11059) Boston, MA 02215 
 
 
Nikhil_Wagle@dfci.harvard.edu  
 
Statistician:    
 
 
William Barry, PhD 
 
 
Department of Biostatistics and Computational Biology 
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave. (CLS 11007) 
 
Boston, MA 02215 
 
Ph: 617-632-2193 
 
Fax: 617-632-5444 
 
Hao Guo, MSc  
Department of Biostatistics and Computational Biology  
Dana-Farber Cancer Institute  
450 Brookline Ave. (CLS 11059) Boston, MA 02215  
Tel: 617-632-3626  
Fax: 617-632-5444  
Email: Hao_Guo@dfci.harvard.edu 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
2 
Study Coordinator:  
 
 
Rebecca Rees 
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave. 
 
Boston, MA 02215 
 
Ph: 617-582-9478 
 
Fax: 617-632-3550 
 
Email: rrees@partners.org 
 
Responsible Research Nurse: 
 
 
TBD 
 
Responsible Data Manager:  
 
N/A 
 
NCI-Supplied Agent(s):  N/A. 
 
Other Agent(s):   
Palbociclib, Pfizer 
Everolimus, Commercial (Novartis) 
Exemestane, Pfizer 
 
 
IND #:  130340/IND Exempt 
IND Sponsor: TBD. 
 
 
Protocol Type / Version # / Version Date: 
Amendment / Version 7 / October 18, 2017 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
3 
SCHEMA 
 
 
Phase Ib Dose Escalation Trial Part 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle Length: 28 days 
 
 
Non-randomized Phase IIa Single Arm Trial Part 
  
Participant characteristics:  
• HR positive and Her2 
negative 
• Progression to CDK 4/6 
inhibitor regimen and to  
NSAI 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N 
 
Cycle Length: 28 days 
 
* Abbreviations: CDK 4/6 – cyclin dependent kinase 4/6; NSAI – non-steroidal aromatase inhibitor.
Start at 
dose level 1 
Treat cohort 
(3 participants) 
Number 
of DLTs 
No further 
escalation
Recruit 3 more 
participants 
Further 
DLTs? 
Stop
Escalate dose 
Yes 
No 
=0 
2 or 3 
Research 
biopsy 
Palbociclib 
+ 
Everolimus 
+ 
Exemestane 
Primary endpoint: Clinical 
Benefit Rate 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
4 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives...................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Breast Cancer Epidemiology ...................................................................................7 
2.2 
Treatment Of Postmenopausal Women With Hormone-Receptor Positive 
Her2 Negative Metastatic Breast Cancer .................................................................7 
2.3 
Cyclin-Dependent Kinases In Breast Cancer ...........................................................8 
2.4 
IND Agent(s) ...........................................................................................................9 
2.5 
Study rationale .......................................................................................................17 
2.6 
Correlative Studies Background ............................................................................18 
3. 
PARTICIPANT SELECTION ...........................................................................................19 
3.1 
Inclusion Criteria ...................................................................................................20 
3.2 
Exclusion Criteria ..................................................................................................22 
3.3 
Inclusion of Women and Minorities ......................................................................23 
4. 
REGISTRATION PROCEDURES ...................................................................................23 
4.1 
General Guidelines for DF/HCC Institutions ........................................................23 
4.2 
Registration Process for DF/HCC Institutions .......................................................24 
4.3 
General Guidelines for Other Investigative Sites ..................................................24 
4.4 
Registration Process for Other Investigative Sites.................................................24 
5. 
TREATMENT PLAN ........................................................................................................24 
5.1 
Treatment Regimen ................................................................................................24 
5.2 
Definition of Dose-Limiting Toxicity (DLT) ........................................................26 
5.3 
Definition of maximum tolerated dose (MTD) ......................................................28 
5.4 
Intra-participant dose escalation ............................................................................28 
5.5 
Doses for Phase II ..................................................................................................28 
5.6 
Pre-Treatment Criteria ...........................................................................................28 
5.7 
Agent Administration.............................................................................................29 
5.8 
General Concomitant Medication and Supportive Care Guidelines ......................30 
5.9 
Criteria for Taking a Participant Off Protocol Therapy .........................................31 
5.10 
Duration of Follow Up ...........................................................................................32 
5.11 
Criteria for Taking a Participant Off Study ...........................................................32 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................33 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................37 
7.1 
Expected toxicities .................................................................................................37 
7.2 
Adverse Event Characteristics ...............................................................................38 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
5 
7.3 
Expedited Adverse Event Reporting ......................................................................39 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................39 
7.5 
Expedited Reporting to Pfizer ................................................................................40 
7.6 
Expedited Reporting to Hospital Risk Management .............................................41 
7.7 
Routine Adverse Event Reporting .........................................................................41 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................41 
8.1 
Palbociclib..............................................................................................................41 
8.2 
Everolimus .............................................................................................................44 
8.3 
Exemestane ............................................................................................................46 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................48 
9.1 
cfDNA Collection ..................................................................................................48 
9.2 
Exome Analysis .....................................................................................................49 
9.3 
Pharmacokinetic Studies ........................................................................................49 
9.4 
Tissue Collection: The molecular underpinnings of CDK 4/6 inhibitors 
response and resistance ..........................................................................................50 
10. 
STUDY CALENDAR .......................................................................................................53 
11. 
MEASUREMENT OF EFFECT........................................................................................56 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................56 
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................63 
12.1 
Data Reporting .......................................................................................................63 
12.2 
Data Safety Monitoring..........................................................................................63 
12.3 
Multicenter Guidelines...........................................................................................63 
12.4 
Collaborative Agreements Language .....................................................................63 
13. 
STATISTICAL CONSIDERATIONS...............................................................................64 
13.1 
Study Design/Endpoints.........................................................................................64 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................65 
13.3 
Stratification Factors ..............................................................................................66 
13.4 
Interim Monitoring Plan ........................................................................................66 
13.5 
Analysis of Primary Endpoints ..............................................................................66 
13.6 
Analysis of Secondary Endpoints ..........................................................................66 
13.7 
Reporting and Exclusions ......................................................................................67 
14. 
PUBLICATION PLAN .....................................................................................................67 
REFERENCES ..............................................................................................................................68 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................76 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................77 
 
APPENDIX C 
DRUG DIARY...........................................................................................84 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
6 
 
 
1. OBJECTIVES 
 
We hypothesize that the treatment of participants with estrogen receptor (ER)-positive and Her2-
negative metastatic breast cancer with palbociclib plus everolimus and exemestane after 
progression to a CDK4/6 inhibitor based regimen and to a non-steroidal aromatase inhibitor will 
be safe, tolerable and lead to improved disease outcomes. 
 
1.1 
Study Design 
 
This is a single center, single arm, open-label, phase Ib/ IIa study. Both parts of the trial (Ib and 
IIa) will be conducted in participants with ER+/Her2− advanced breast cancer that progressed on 
a CDK 4/6 inhibitor regimen and a NSAI.  
 
The phase Ib part of the study is designed to estimate the maximum tolerated dose (MTD) and/or 
the recommended phase II dose (RP2D) for the combination of palbociclib with everolimus and 
exemestane (P-E-E). The phase Ib part of the study will also assess the safety and tolerability of 
the P-E-E combination, including PK of everolimus and palbociclib in the triple combination. It 
will be followed by a phase IIa part to assess the clinical safety, tolerability and efficacy of the 
triple combination of P-E-E in participants with ER+, Her2− advanced breast cancer refractory to 
a prior CDK 4/6 inhibitor regimen and to a NSAI. 
 
Each cycle will be 28 days with Palbociclib administered orally, once daily for 21 consecutive 
days followed by a 7-day break; everolimus and exemestane will be administered orally, once 
daily on a 28 day schedule. Participants will be re-staged every 8 weeks and are permitted to be 
treated until progression of disease, development of unacceptable toxicity, withdrawal of informed 
consent or death, whichever occurs first. If clinical benefit rate (CBR) of the combination is equal 
or superior to 65%, the regimen will be considered worthy of further study. 
 
1.2 
Primary Objectives 
 
• Phase Ib: To describe the safety and tolerability and define MTD/RP2D of palbociclib in 
combination with everolimus and exemestane in participants with ER+ Her2− advanced 
breast cancer; 
• Phase IIa: To estimate the activity of palbociclib in combination with everolimus and 
exemestane, as defined by clinical benefit rate (CBR), in participants with ER+ Her2− 
advanced breast cancer. 
 
 
1.3 
Secondary Objectives 
 
• Phase Ib: To describe the PK profile of everolimus and palbociclib in the triple combination 
and evaluate the DDI potential (effect of palbociclib on the PK profile of everolimus); 
• Phase Ib and IIa: To investigate biomarkers of sensitivity and resistance to CDK 4/6 
inhibitors at the DNA, RNA and protein levels respectively via whole exome sequencing, 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
7 
RNA Seq and immunohistochemistry of paired tumor biopsies; 
• Phase IIa: To estimate the activity of palbociclib in combination with everolimus and 
exemestane, as defined by overall response rate (ORR), disease control rate (DCR), 
duration of response (DOR) and progression free-survival (PFS) according to investigator 
assessment, in participants with ER+ Her2− advanced breast cancer. 
 
 
2. BACKGROUND 
 
2.1 
Breast Cancer Epidemiology 
 
Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer related 
deaths in women worldwide, accounting for 23% (1.38 million) of all new cancer cases and 14% 
of cancer deaths (more than 400,000) each year.1 
 
In the US, the estimated incidence of BC is 122.2 cases per 100 000 women per year leading to 
the diagnosis of approximately 233,000 new cases of invasive BC in 2014, of which about 40,000 
women are expected to die from.2 Furthermore, approximately 40% of those participants treated 
with curative intent will eventually develop metastatic BC.3 For women with metastatic disease, 
treatment is palliative and overall median life expectancy, despite varying between subtypes of 
BC, ranges from 17 to 54 months.4 
 
2.2 
Treatment Of Postmenopausal Women With Hormone-Receptor Positive Her2 Negative Metastatic 
Breast Cancer 
 
Expression of the estrogen receptor (ER) and/or progesterone receptor (PgR) is present in up to 
70% of the cases of BC and is a strong prognostic marker.5 Estrogen deprivation is the backbone 
of treatment in participants with hormone receptor positive (HR+) Her2 negative advanced BC 
and ER expression is the strongest predictor of response to such endocrine therapies.6,7 
Postmenopausal women account for more than 80% of the women with BC, and in such group 
endocrine therapy options for those ER+ advanced BC (locally advanced, recurrent, or metastatic 
BC) include selective estrogen receptor modulators (SERM; tamoxifen), estrogen receptor 
antagonists (fulvestrant), selective nonsteroidal aromatase inhibitors (NSAI; anastrozole and 
letrozole) and steroidal aromatase inhibitors (exemestane).8 Blocking estrogen signaling with 
tamoxifen has been the main approach in treatment for ER positive BC for over 30 years. 
Tamoxifen is indicated for the treatment across the whole continuum of HR+ BC in premenopausal 
women, ranging from risk reduction in women at high risk of developing BC to treatment of 
metastatic disease. In postmenopausal women, aromatase inhibitors (AI) reduce peripheral 
estrogen synthesis by blocking the conversion of androgens to estrogens in non-ovarian tissues; 
synthesis in these tissues is the primary source of estrogens in postmenopausal women. Aromatase 
inhibitors are generally used as the first option of therapy for postmenopausal women with ER+ 
BC, both in the adjuvant and metastatic setting.9,8,10,11 Despite the broad spectrum of available 
options for participants with ER+ advanced BC, most eventually develop resistance to hormonal 
deprivation. One mechanism of endocrine resistance is aberrant signaling via phosphatidylinositol 
3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway.12,13 Hyperactivation of 
PI3K/mTOR is observed in endocrine-resistant BC cells, and treatment with mTOR inhibitors, 
including rapamycin analogs, reverses this resistance.14 Growing evidence also supports a close 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
8 
interaction of the mTOR pathway with ER signaling. S6 kinase-1 (S6K1), a substrate of mTOR 
Complex 1 (mTORC1), phosphorylates the activation domain AF-1 of the ER, and stimulates 
ligand-independent activation of the receptor.15,16 Everolimus is a rapamycin derivative that 
inhibits mTORC1 through allosteric binding; it does not inhibit mTORC2.17 Everolimus combined 
with AIs in preclinical models of ER-positive (ER+), hormone-sensitive and hormone-resistant 
BC results in G1 arrest and enhanced apoptosis.18 In the clinical arena, everolimus combined with 
exemestane is active in participants with advanced ER+ BC resistant to previous hormonal 
deprivation therapy with nonsteroidal  aromatase  inhibitor, either  in  the adjuvant setting or to 
treat advanced disease (the BOLERO-2 study19). Although treatment options with targeted agents 
has expanded, cytotoxic agents, typically anthracyclines and taxanes and more recently 
capecitabine, are also used to treat participants with a significant tumor burden and symptomatic 
visceral disease. Capecitabine monotherapy in participants without previous exposure to taxanes 
and anthracyclines showed PFS between 4.1 and 7.9 months, and OS between 18.6 and 29.4 
months 20–24, and is included in treatment guidelines as an effective option for first line treatment 
in participants with advanced BC. More recently, CDK 4/6 inhibitors joined the therapeutics 
portfolio for this subset of participants, as discussed ahead. 
 
2.3 
Cyclin-Dependent Kinases In Breast Cancer 
 
The cell cycle includes a set of consecutive phases that ultimately lead to mitosis; in this setting, a 
group of kinases, referred as cyclin-dependent kinases, and their regulatory counterpart, referred 
as cyclins, have a central governing role.25 Cyclin D, in association with CDK4/6, controls the 
early transition of the cell cycle between G1 and S phases, thus setting an early checkpoint in cell 
cycle. In specific, the interaction of cyclin D with CDK4/6 leads to the activation of the kinase 
activity of the latter. A widely recognized target of this complex is the tumor suppressor Rb (and 
other Rb 'pocket' protein family members, such as p130 and p107) that is inactivated after CDK4/6 
mediated phosphorylation (revised in refs26,27). As a consequence, downstream E2F family 
transcription factors are released, and E2F‑responsive genes activated. This activation leads to the 
expression of a plethora of genes essential for DNA synthesis and continuing cell cycle 
progression. Strong preclinical28,29 and clinical evidence30–32 support the relevance of this target 
for cancer therapy, in specific for ER-positive BC. Data from The Cancer Genome Atlas highlight 
the importance of the Cyclin/CDK/Rb pathway in luminal BC.33 Abnormalities that result in CDK 
activation are highly enriched in the luminal A and B molecularly defined subgroups, ~85% of 
which were ER+/Her2−. Cyclin D1 amplifications were observed in 29% and 58% of the luminal 
A and B subtypes, respectively, and CDK4 amplifications were observed in 14% and 25% of 
luminal A and B subtypes, respectively. Luminal A subtype tumors also have loss of CDKN2. The 
luminal subtypes maintain expression of Rb33, which would be essential for clinical benefit from 
treatment targeting this pathway, as a CDK4/6 inhibitor. A recent phase II trial led to the 
conditional approval by the US Food and Drug Administration of palbociclib, an oral, potent, 
CDK4/6 inhibitor, in association with letrozole (a NSAI) as first-line treatment for metastatic ER-
positive, HER2-negative BC.31 Unfortunately, despite the initial benefit derived from the addition 
of palbociclib for the overall sample of luminal BC participants enrolled in this trial (median 
progression free-survival of approximately 20 months compared to 10 months in the letrozole 
monotherapy arm), after 3 years of study enrollment more than 70% of the participants had a 
disease progression event (secondary resistance). Achieving improved disease control with 
endocrine therapy-based regimens is still an unmet medical need for this participant population. 


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The co-administration of agents targeting the PI3K/mTOR pathway and agents targeting the 
CDK4/6 pathway is still a relatively unexplored concept in the context of progression to first line 
ET in combination with palbociclib (study rationale detailed in Section 2.5). 
 
2.4 
IND Agent(s) 
 
2.4.1 
Palbociclib 
 
Palbociclib (PD-0332991), 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.34–36 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 p16.37–41 
Overexpression of p16 in cells with normal Rb inhibits both CDK4 and CDK6-associated kinase 
activity and Rb phosphorylation, with subsequent cell cycle arrest.42,43 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.44 Cyclin D1 is a direct transcriptional target of ER45,46 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 expression47, while endocrine resistance is associated with persistent cyclin D1 expression and 
Rb phosphorylation.48 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 activity49 and CDK4/6 
inhibitors are most effective in tumors with gene amplification and overexpression of cyclin 
D128,50,51, which is common in ER+ breast cancer. Genetic aberrations leading to hyperactivation 
of cyclin D1-CDK4/6 is particularly common in ER+ breast cancer29, consistent with its critical 
role in the tumorigenesis of this cancer subtype, making CDK4/6 inhibitors particularly attractive 
agents for ER+ breast cancer. 
 
2.4.1.1 
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 vivo28 
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.28 Treatment 
of cultured tumor cells with palbociclib causes growth arrest that is accompanied by the inhibition 
of specific Rb phosphorylation by CDK4 or CDK6 on residues serine -780 and -795 of Rb. The 
IC50 values for reduction of Rb 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 Rb 
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 


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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. 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 metabolizing 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. 
 
2.4.1.2 
Palbociclib Pharmacokinetic (PK) Data 
 
Pharmacokinetic data have been collected in at least 8 clinical studies for a total of over 250 
advanced cancer participants 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, 


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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 
participants 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 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 
approximately 37% 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.  
 
2.4.1.3 
Palbociclib Dose Rationale  
 


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Palbociclib has been used in a Phase 1 dose escalation Study (A5481001) in 74 participants with 
advanced cancer. Two dosing schedules were evaluated: a 3/1 (3 weeks on treatment/1 week off 
treatment) schedule and a 2/1 (2 weeks on treatment/1 week off treatment) schedule. 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, the observed neutropenia was reversible and non-cumulative. The most common 
nonhematological adverse events included fatigue, anemia, diarrhea, constipation, vomiting and 
dyspnea, all with mild to moderate severity. A greater proportion of participants on the 2/1 
schedule had treatment emergent adverse events (TEAEs) than participants on the 3/1 schedule 
although the proportion of participants with treatment related neutropenia was similar with respect 
to the 2 dosing schedules both. On this trial (A5481001) a total of 13/37 participants treated with 
Schedule 3/1 evaluable for efficacy experienced stable disease (SD), including 6 participants with 
SD lasting 40 weeks or longer. One of these participants was a woman with ER+ breast cancer 
who had previously received 7 lines of treatment for her disease. This participant 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. Additionally, one partial response (PR) was reported in a 
participant with testicular cancer. Based on the relatively improved safety profile of the 3/1 
schedule, and the efficacy results from this study, the 3/1 schedule has been selected for further 
clinical development.  The RP2D for this schedule was determined to be 125 mg/day and was 
further explored in combination with letrozole in the Phase I/II study in participants with advanced 
breast cancer described below.  
1 
2.4.1.4 
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 Annual Meeting from 28 
women who have completed cycle 1.52 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 participant with six previous chemotherapy regimens. All other toxicities were grade 
1/2. Treatment was interrupted in 7 (25%) and dose reduced in 13 (46%) participants for 
cytopenias; 27/28 participants discontinued study for disease progression. The (PR + SD) >6 
months was as follows: 4 participants (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 participants 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 


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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 participants with ER+/HER2-negative advanced 
breast cancer. The Phase II portion, also called PALOMA-1, consisted of 2 parts. In Part 1, 
participant selection was based only on ER/HER2 status. In Part 2, participants were prospectively 
selected also taking into account tumor CCND1 amplification and/or p16 loss. A total of 177 
participants 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 participants with measurable disease (3 had bone-only disease). Another 5 
participants (42%) had stable disease for ≥ 6 months and the clinical benefit rate (PR + SD ≥ 6 
months) was 67%. Eight (8) participants discontinued from the study due to disease progression, 
including 2 participants with clinical progression, 1 participant withdrew consent, and 3 
participants were still being followed. 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).53 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).31 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 participants 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 participant 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.  
 
Please refer to the Full Prescribing Information for palbociclib for complete safety information: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.   
 
 
2.4.2 
Everolimus 
 
Everolimus (RAD001) has been in clinical development since 1996 as an immunosuppressant in 
solid organ transplantation. Everolimus is approved in the United States for the prevention of organ 
rejection of kidney transplantation. In 2012 everolimus in combination with exemestane was 
approved for advanced breast cancer in the US, EU and other countries. Everolimus is a derivative 
of rapamycin. It is a selective mTOR inhibitor, specifically targeting the mTOR-raptor (regulatory-
associated protein of mTOR, Raptor) signal transduction complex 1 (mTORC1). Everolimus 


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potently inhibits proliferation of endothelial cells54,55 and has antiangiogenic activity in vivo.55–58 
 
2.4.2.1 
Everolimus Preclinical Data 
 
Everolimus inhibits the proliferation of a wide range of human tumor cell lines in vitro at IC50s 
ranging from sub/low nM to µM. The antitumor efficacy of everolimus was compared to other 
compounds in a panel of six breast cancer xenograft models established after direct transplantation 
of participants’ tumors onto nude mice [Report RD-2011-50492]. This panel included an ER+ 
model, HBCx-3 (XTS-181).59 Everolimus given daily by oral gavage for 21 to 35 days at 20 mg/kg 
was well tolerated with no significant mean body weight loss. In all breast cancer models tested, 
tumor growth was significantly inhibited, and was particularly evident in the HBCx-3 (XTS-181) 
model with nine partial regressions in ten mice tested (-13.5% mean tumor volume regression, 
p<0.001). Based on data generated using human liver microsomes and microsomes from cells 
expressing single human cytochrome P450s enzymes, CYP3A4 was identified as the major 
enzyme involved in the microsomal biotransformation of everolimus. Everolimus inhibited 
competitively the metabolism of the CYP3A4 substrate cyclosporine with a Ki value of 2.3µmol/L 
(2204 ng/mL) under in vitro conditions. 
 
2.4.2.2 
Everolimus Pharmacokinetic (PK) Data 
 
Everolimus is rapidly absorbed with a median tmax of one to two hours. The steady-state AUC0-τ is 
dose-proportional over the dose ranges between 5 to 70 mg when given weekly and 5 and 10 mg 
when given daily. Steady-state was achieved within two weeks with the daily dosing regimen. Cmax 
is dose-proportional between 5 and 10 mg for both the weekly and daily regimens. In healthy 
subjects, high fat meals reduced systemic exposure to a 10 mg dose of everolimus (as measured 
by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals reduced AUC 
by 32% and Cmax by 42%. Food had no apparent effect on the post absorption phase concentration-
time profile (Study RAD001C2120). The blood-to-plasma ratio of everolimus, which is 
concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of 
everolimus confined to the plasma is approximately 20% at blood concentrations observed in 
cancer participants given everolimus 10 mg/day (DMPK R303044). Plasma protein binding is 
similar in healthy participants and in subjects with moderate hepatic impairment (approximately 
74%, [Study RAD001A2303]). The major and nearly exclusive enzyme responsible for the 
metabolism of everolimus in man was CYP3A4 (DMPK (US) 1998/005; DMPK (CH) R99-
2448).60 Other CYP isoenzymes either do not metabolize everolimus or do so at very low rates. 
Everolimus is a moderate inhibitor of P-glycoprotein-like mediated efflux systems, although the 
compound has a high intrinsic permeability when P-glycoprotein is inhibited (DMPK (CH) 
1997/417).61,62 Following oral administration, everolimus is the main circulating component in 
human blood and contributes the majority of the overall pharmacologic activity (Study W107). 
Everolimus was also shown to increase exposure of exemestane: In [Study RAD001Y2301], 
average exemestane Cmin and C2h were 45% and 71% higher, respectively, when co-administered 
with everolimus. No specific excretion studies have been undertaken in cancer participants; 
however, data available from the transplantation setting found the drug to be mainly eliminated 
through the feces. 
 
2.4.2.3 
Everolimus Clinical Data 
 


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Everolimus as single agent 
In a multicenter, randomized phase II study, a daily dose of everolimus (10 mg) was evaluated in 
participants with advanced breast cancer, most commonly with ER+ disease previously treated 
with hormonal deprivation therapy. In the subgroup of 19 participants with ER-positive/human 
epidermal growth factor receptor 2 (Her2)-negative in this trial, one complete response, 2 partial 
responses, 3 stable disease for longer than 6 months, and 6 stable disease for less than 6 months 
were observed. Median progression-free survival (PFS) in this subset of 19 participants was 3.5 
months (95% C.I.: 1.9 – 5.5 months, data source: NCI-Canada). An additional partial response was 
reported in a participant with ER-positive Her2−unknown disease.63 
 
Everolimus in combination with endocrine therapy in ER+ breast cancer 
The combination of everolimus with hormonal therapy has been assessed in different disease 
settings. In newly diagnosed participants with ER+ breast cancer, a neoadjuvant randomized 270-
participant phase II study compared the combination of everolimus 10 mg QD and letrozole 2.5 
mg QD to letrozole alone for 16 weeks of therapy prior to surgery. The overall response rate in the 
investigational everolimus + letrozole arm was higher than that with letrozole alone: 68% vs. 59% 
based on palpation (p = 0.062) and 58% vs. 47% based on ultrasound (p= 0.021) respectively, 
meeting the predetermined endpoint for efficacy. Additionally, there was a greater antiproliferative 
response in the investigational arm, with a decrease of the Ki67 proliferation index to <1 in 57% 
of participants in the everolimus arm compared to 30% of participants in the placebo arm 
(p<0.01).64 A randomized phase III, double-blind, placebo-controlled study (the BOLERO-2 
Study) demonstrated very significant improvements in treatment of HR+ breast cancer that had 
recurred or progressed on letrozole or anastrozole. Response rate, PFS, and clinical benefit rate 
were all significantly improved relative to exemestane monotherapy. The median progression-free 
survival (PFS) by local assessment was 7.8 months for everolimus + exemestane versus 3.2 months 
for exemestane (HR = 0.45; 95% CI: 0.38-0.54; P<.0001). Overall response rate (12.6 % vs 1.7%; 
P<.0001) and clinical benefit rate (51.3% vs 26.4%; P<.0001) were superior in the everolimus + 
exemestane arm versus exemestane + placebo. Analyses by central assessment showed a median 
progression-free survival of 11 months with everolimus versus 4.1 months with placebo (HR = 
0.38; 95% CI: 0.31 – 0.48; P <.0001) confirming the results of the primary PFS analysis.19  
 
Safety profile 
The following adverse events are considered to be class-effects of mTOR inhibitors: stomatitis/oral 
mucositis/ulcers, infections and infestations, rash and similar events, cytopenia, hemorrhages, non-
infectious pneumonitis, hyperglycemia/new-onset diabetes mellitus, renal events, and 
thromboembolism. The more common metabolic side effects reported with mTOR inhibitors result 
from inhibitory effects on mTOR-regulated lipid and glucose pathways, while infections stem from 
the immunosuppressive properties of these agents. Virtually all of the side effects associated with 
mTOR inhibitors can be managed effectively with dose modification and/or supportive 
intervention. The safety profile of everolimus observed in the phase III BOLERO-2 study is 
consistent with prior experience in the oncology setting; events are predominantly low grade 
(grade 1 or 2). An increased risk of non-infectious pneumonitis, infection, and stomatitis in the 
everolimus plus exemestane arm relative to the control arm [exemestane + placebo] was observed, 
although each of these events can be effectively managed in this setting. The most common adverse 
events (AEs) suspected to be related to treatment, with an incidence ≥10%, reported in association 
with everolimus plus exemestane therapy were consistent with what was previously reported: 


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stomatitis, rash, fatigue, decreased appetite, diarrhea, dysgeusia, nausea, pneumonitis, weight loss, 
anemia, epistaxis, hyperglycemia, thrombocytopenia, and pruritus. The most common grade 3-4 
AEs suspected to be related to treatment with an incidence of ≥2% were: stomatitis, 
hyperglycemia, anemia, pneumonitis, fatigue, elevated alanine and aspartate transaminase 
concentrations, elevated γ-glutamyltransferase concentrations, dyspnea, neutropenia, and 
thrombocytopenia. No new safety concerns have emerged compared to previous experience with 
everolimus monotherapy or combination therapy.  
 
Please refer to the Full Prescribing Information for everolimus for complete safety information: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.   
 
 
2.4.3 
Exemestane 
 
Exemestane is an irreversible steroidal aromatase inhibitor that has demonstrated efficacy in the 
treatment of postmenopausal participants with advanced breast cancer. It is indicated for adjuvant 
treatment of postmenopausal women with ER+ early breast cancer who have received two to three 
years of tamoxifen and are switched to exemestane for completion of a total of five consecutive 
years of adjuvant hormonal therapy. As an off-label indication, it is also commonly given as 
adjuvant endocrine therapy in monotherapy for a total period of 5 years. It is further indicated for 
the treatment of advanced breast cancer in postmenopausal women whose disease has progressed 
following tamoxifen therapy. Exemestane is initially recognized by the aromatase enzyme as a 
false substrate and is then transformed through an NADPH-dependent mechanism to an 
intermediate that binds irreversibly to the enzyme, causing inactivation. Exemestane significantly 
lowers circulating estrogen concentrations (estradiol, estrone and estrone sulfate), but has no 
detectable effect on adrenal biosynthesis of corticosteroids or aldosterone (Aromasin prescribing 
information Pfizer-Pharmacia 2005). The recommended daily dose of exemestane is 25 mg via 
oral administration. Exemestane is rapidly absorbed from the gastrointestinal tract. Its 
bioavailability is limited by first-pass metabolism, but is increased when taken with food. 
Exemestane is widely distributed, and is extensively bound to plasma proteins. The terminal half-
life for exemestane is 18-24 hours. The time needed to reach maximal E2 suppression is 7 days.65–
67 Exemestane is metabolized by CYP3A4 and aldoketoreductases. It does not inhibit any of the 
major CYP isoenzymes, including CYP 1A2, 2C9, 2D6, 2E1 and 3A4. Although no formal drug-
drug interaction studies have been conducted, significant effects on exemestane clearance by CYP 
isoenzyme inhibitors appear unlikely (Aromasin prescribing information Pfizer-Pharmacia 
2011).67,68 As noted in Section 2.4.2.2, everolimus increases exposure of exemestane. The most 
frequently reported adverse effects for exemestane are gastrointestinal disturbances, hot flashes, 
arthralgia, myalgia, sweating, fatigue, and dizziness. Other reported effects include headache, 
insomnia, somnolence, depression, skin rashes, alopecia, asthenia, and peripheral and leg edema. 
Thrombocytopenia and leukopenia have been reported occasionally. Reductions in bone mineral 
density can occur with long-term use of exemestane. A total of 1058 participants were treated with 
exemestane 25 mg once daily in the clinical trials program. Exemestane was generally well 
tolerated, and adverse events were usually mild to moderate. Adverse events occurring in greater 
than 10% of participants include hot flashes (14%), nausea (11.9%), insomnia, headache, increased 
sweating, joint and musculoskeletal pain, and fatigue (USPI Aromasin SmPC August 2008 [UK 
as RMS for EU MRP]). Androgenic effects were reported in a limited number of participants 


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(4.3%).67  
 
Please refer to the Full Prescribing Information for exemestane for complete safety information: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.   
 
 
2.5 
Study rationale 
 
Endocrine therapy is the backbone therapy of ER-positive advanced breast cancer. In 
postmenopausal women, the use of NSAI is a common, effective and well established treatment 
option, being associated with good tolerability and clinical benefit.69,70 
 
A recent phase II trial (PALOMA-2) further showed that the clinical benefit of NSAI monotherapy 
for metastatic ER-positive, HER2-negative BC can be additionally enhanced with the association 
of palbociclib, an oral, potent, CDK4/6 inhibitor.31 With a median follow-up of almost 30 months, 
median progression free-survival (PFS) of the combination arm was of 20.2 month compared to 
10.2 months in the letrozole monotherapy arm. Subsequently, a combination of palbociclib with 
fulvestrant further demonstrated improved outcomes in participants showing clinical resistance to 
an NSAI (PALOMA-3; either relapsing during or within 12 months after adjuvant endocrine 
therapy or progression on NSAI in the metastatic setting). At a preplanned interim analysis after 
195 events of disease progression or death, median PFS was of 9.2 months with palbociclib in 
association with fulvestrant and 3.8 months with fulvestrant plus placebo. As a matter of fact, 
abnormalities that result in CDK activation and thus Cyclin D-CDK 4/6-Rb-E2F pathway 
activation are frequent in the luminal A and B molecularly defined breast cancer.33 Unfortunately, 
despite the unprecedented benefit derived from the addition of palbociclib to letrozole in 
PALOMA-1, after 3 years of study enrollment, more than 70% of the participants had a disease 
progression event (either due to primary or secondary resistance). Similarly, in PALOMA-3, after 
1 year of study enrollment more than 65% of the participants had a disease progression event. 
Therefore, improving disease control with endocrine therapy-based regimens is still an unmet 
medical need.  
 
PI3K-AKT-mTOR pathway aberrations are a common molecular finding in breast cancer, being 
present in up to half of these tumors (the majority involving the PIK3CA gene, but also PTEN and 
AKT).71 These aberrations have been identified as a mechanism of resistance to endocrine 
therapy.15,16,72 In this context, everolimus, an agent from a class of drugs targeting mTOR (a 
downstream target of PI3K), demonstrated clinical benefit in those participants with HR-positive 
advanced breast cancer who were refractory to a NSAI (BOLERO-2).19 In that study, the 
combination of everolimus plus exemestane was associated with a median progression-free 
survival of 10.6 months, which compared to a median PFS of 4.1 months with single agent 
exemestane (HR 0.36; 95% CI: 0.27 to 0.47; P<0.001).  
 
The co-administration of agents targeting the PI3K/mTOR pathway and agents targeting the 
CDK4/6 pathway is still a relatively unexplored avenue, especially in the setting of progression to 
a previous CDK 4/6 inhibitor regimen and a prior NSAI in participants with advanced ER-positive 
Her2-negative BC. Remarkably, preclinical data showed that the addition of PI3K/mTOR pathway 
inhibitors to CDK4/6 inhibitors seems a promising strategy, both by increasing CDK 4/6 inhibitors 


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18 
lethality73 or overcoming PI3K/mTOR pathway inhibitors resistance74. These data constitutes the 
clinical and preclinical motivation for this trial. Therefore, the purpose of this study is to evaluate 
the safety and tolerability of the investigational combination of palbociclib plus everolimus plus 
exemestane in postmenopausal women with ER+ Her2- metastatic breast cancer progressing to 
previous CDK 4/6 inhibitor and to an NSAI. Furthermore, this study will also evaluate the efficacy 
of this investigational combination as measured by its CBR. 
 
2.6 
Correlative Studies Background 
 
In this study we plan to perform a correlative sub-study as detailed bellow. Technical details are 
further discussed in Section 9. 
 
The molecular underpinnings of CDK 4/6 inhibitors response and resistance 
Cyclin D is an essential element in the governance of the p16-cyclin D/CDK-Rb-E2F pathway, 
thus being an appealing target for cancer therapy.75 As a matter of fact, strong preclinical28,29 and 
clinical evidence30–32,76 support the relevance of this target for cancer therapy, especially for 
luminal BC. Unfortunately, primary and secondary resistance to CDK4/6 inhibitors significantly 
hampers sustained treatment benefit, as demonstrated in two recent clinical trials: in PALOMA-2 
(palbociclib plus letrozole as first line metastatic therapy), after 3 years of study enrollment, more 
than 70% of the participants had a disease progression event; similarly, in PALOMA-3 
(palbociclib plus fulvestrant in participants refractory to NSAI), after 1 year of study enrollment 
more than 65% of the participants had a disease progression event.  
 
To appropriately target CDK 4/6 inhibitors therapy and obviate the limitations of primary and 
secondary resistance, Finn and colleagues performed preclinical evaluations of palbociclib in a 
group of 44 human BC cell lines. This seminal study identified promising biomarkers to tailor 
palbociclib therapy, such as the ER.29 Curiously, while palbociclib acted mostly as a cytostatic in 
ER+ cellular models, it had a synergistic cytotoxic activity when associated to tamoxifen. 
Furthermore, palbociclib was also able to partially revert tamoxifen resistance. In the same work, 
high levels of cyclin D1 and Rb and low levels of p16 were also associated with higher sensitivity 
to palbociclib. Also, while sensitive cell lines responded to palbociclib with an increase of 
phosphorylated Rb (“switching” Rb off), resistant cell lines did not reveal a change in Rb 
phosphorylation status. This fact constituted a strong proof of concept of the dependence of 
palbociclib action from the p16-cyclin D/CDK-Rb-E2F pathway. Such failure of palbociclib to 
dephosphorylate Rb in resistance cell lines could be due to several reasons, as mutations of 
CDK4/6, other mechanisms driving Rb hyperphosphorylation (as greater dependence on CDK1/2-
cyclin E interactions) and/or loss of negative regulators of p16-cyclin D/CDK-Rb-E2F pathway.29  
 
Building on the available preclinical evidence of efficacy and biomarkers, the palbociclib pivotal 
phase II trial presented a novel design.31 In that trial, two independent cohorts accrued sequentially: 
cohort 1 composed of participants with ER+/HER2- breast cancers, and cohort 2 equally composed 
of participants with ER+/HER2- tumors, but also positive for cyclin D1 amplification, p16 loss, or 
both. Despite the selection of participants restricted to those with ER+ tumors (not allowing the 
comparison with other subtypes of breast cancer), the unprecedented benefit from palbociclib plus 
letrozole when compared to letrozole alone favors an especially high sensitivity of this BC subtype 
to CDK4/6 manipulation. Of note, the preclinical analysis from Finn and colleagues also suggested 


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that ER+/HER2+ tumors might benefit from cyclin D-CDK4/6 inhibition with palbociclib, a 
hypothesis still being explored. Disappointingly, the enrichment in cohort 2 for participants with 
markers of anticipated benefit from palbociclib did not improve outcomes in the arm receiving 
palbociclib. Intriguingly, the arm of cohort 2 receiving letrozole as monotherapy presented 
remarkable outcomes.  
 
On the other side of the coin are a group of BC features that render tumors resistant to palbociclib. 
Still on the basis of the seminal work by Finn and colleagues, non-luminal/basal intrinsic subtype 
breast cancer seem to be resistant to palbociclib29, a feature that might be explained by the frequent 
loss of Rb in basal subtype BC.77 As a matter of fact, G1/S phase transitions do not seem to be 
controlled by cyclin D1 in the absence of a functional Rb.78 Dean and colleagues further extended 
this work body using a panel of Rb knockdown immortalized human breast epithelial cells and 
several BC cell lines.79 In this cellular model, while Rb proficient cells treated with palbociclib 
had a strong decline of cell division, acute response to palbociclib was greatly impaired by the 
absence of Rb, which supports the relevance of Rb integrity for palbociclib response. Of note, 
palbociclib still exerted a partial cytostatic effect in cell lines deprived of Rb (even though lower 
than in Rb-proficient cells), challenging the idea that Rb is the only mediator of response to 
palbociclib. In this setting, an elevation of p107 levels was noted, and the authors propose that it 
may constitute a route for partial repression of E2F-target genes. Furthermore, cell lines resistance 
to palbociclib after chronic treatment with CDK4/6 inhibition, frequently presented increased 
levels of p107 and CDK2 protein and/or loss of p21 and p27.79 Curiously, in this setting, loss of 
p21/p27 was due to a post-transcriptional mechanism (not at transcriptional level), a finding 
already documented in certain breast cancers, in which loss of p27 is associated with poor 
prognosis. As a consequence, the authors suggest that p27 loss could serve as a marker of both BC 
with poor prognosis and resistance to CDK 4/6 inhibition. Moreover, E2F overexpression led to a 
complete resistance to palbociclib, a phenomenon independent from Rb status.79 Interestingly, in 
Rb proficient cells, forcing E2F overexpression led to Rb phosphorylation. Finally, palbociclib 
treatment might lead to cyclin D1 stabilization and accumulation (probably due to delayed 
turnover).79 As a consequence, limiting doses of palbociclib could result in a rapid activation of 
CDK4/6. Finally, p53 may also play a relevant role as a marker of response to CDK4/6 inhibitors. 
Remarkably, p53 is a known regulator of CDK480,81, and interesting findings from ovarian and 
brainstem glioma models found that p53 mutation is correlated with CDK 4/6 inhibitors 
resistance.82,83 
 
In this sub-study we aim to characterize the molecular underpinnings of CDK4/6 resistance using 
paired biopsies at baseline and disease progression, as successfully performed in other settings.84–
87 The evaluation will focus on the p16-cyclin D/CDK-Rb-E2F and p53 pathways to seek 
exploratory correlations with clinical response. 
 
 
3. PARTICIPANT SELECTION 
 
Participants must meet the following criteria on screening examination to be eligible to participate 
in the study. Laboratory tests required for eligibility must be completed within 14 days prior to the 
date of registration. Diagnostic tests, such as MRIs and CT scans, must be performed within 30 
days of registration and baseline measurements must be documented within 14 days of the date of 


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20 
registration. 
 
3.1 
Inclusion Criteria  
 
3.1.1 Participants with histologically or cytologically confirmed hormone receptor (HR)-
positive, Her2-negative metastatic breast cancer. Central confirmation of HR positivity 
is not required 
 
3.1.2 Postmenopausal women as defined as:  
 Age >60 years 
or 
 Age >45 with intact uterus and amenorrhea for >12 consecutive months or 
Follicle stimulating hormone (FSH) levels within postmenopausal range 
according to the ranges established by the testing facility 
or 
 Premenopausal women who have been on a GnRH agonist for at least 6 weeks 
prior to study entry. Women in this group MUST remain on the GnRH agonist 
for the duration of protocol treatment 
or 
 Status post bilateral oophorectomy, after adequate healing post surgery; 
 
3.1.3 Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study entry. 
Men MUST remain on the GnRH agonist for the duration of protocol treatment. 
 
3.1.4 Participants enrolled  in the Phase I portion must have evaluable disease.  Participants 
enrolled in the Phase II portion must have measurable disease as per RECIST 1.1.  
 
3.1.5 Prior Treatment Specifics: 
• Participants must have radiological or objective evidence of progression to a 
CDK4/6 inhibitor regimen in the metastatic setting AND relapse/progression on an 
NSAI (defined as either relapsed ≤ 12 months after completing adjuvant NSAI or 
progressed through an NSAI for metastatic or locally advanced breast cancer) 
• Participants may have received any number of previous endocrine/hormonal lines 
of therapy in the metastatic setting, as long none of them were exemestane-based 
and the last dose is ≥ 14 days prior to registration; 
• Participants may have received any CDK4/6 inhibitor (i.e. palbociclib, ribociclib, 
abemacicliclib, etc) as long as the last dose is ≥ 14 days prior to registration; 
• Participants may have received up to one prior chemotherapy line for advanced 
breast cancer as long as the last dose is ≥ 21 days prior to registration; 
• Participants may have received prior biologic treatments or investigational drugs as 
long as the last dose is ≥ 21 days prior to registration; 
• Participants may have received radiotherapy for palliative purposes but must not be 
experiencing > grade 1 treatment related toxicies and have completed treatment ≥ 
14 days prior to registration 
 


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21 
3.1.6 Age ≥18 years.  Age restriction applies given that no dosing or adverse event data are 
currently available on the use of palbociclib or exemestane in participants <18 years of 
age.  
 
3.1.7 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.8 For participants enrolling the phase IIa part of the study, accessible tumor lesion(s) for 
the purpose of research biopsy and willingness to undergo a research biopsy before 
treatment initiation and at the time of disease progression, as well as a single research 
blood sample before initiation of therapy.  Participants who undergo an attempted on-
treatment research biopsy and in whom inadequate tissue is obtained are still eligible to 
receive protocol therapy.  They will not be required to undergo a repeat research biopsy 
attempt.  
 
3.1.9 For participants enrolling the phase Ib part of the study, willingness to provide archival 
tumor samples when available. 
  
3.1.10 Participants must have normal organ and marrow function, as defined below: 
 
− 
absolute neutrophil count 
≥1.5x109/L 
− 
platelets 
≥100 x109/L 
− 
total hemoglobin 
≥ 9 g/dL (which may be post transfusion)  
− 
total bilirubin 
≤1.5 x institutional upper limit of normal 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal or ≤5 × 
institutional upper limit of normal for participants with 
liver metastases 
− 
creatinine 
≤1.5 x above institutional normal or ≥ 60 ml/min/1.73m2 
for subjects with creatinine levels above institutional 
normal. 
− 
baseline QTc  
< 500 ms 
− 
fasting plasma glucose 
 <140 mg/dL / 7.8 mmol/L 
 
3.1.11 The effects of the combination of palbociclib, everolimus and exemestane on the 
developing human fetus are unknown.  Given that women in this study will be post-
menopausal by eligibility criteria (de facto or pharmacologically induced), it is expected 
that there will be no women of child-bearing potential in this study. 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. Of note, premenopausal 
women and men are only eligible if they have been on a GnRH agonist for at least 6 weeks 
prior to study entry. These participants MUST remain on the GnRH agonist for the duration 
of protocol treatment. Such participants should be counseled prior to study entry that GnRH 
agonists alone may not be adequate contraception and that adequate contraception (barrier 
method of birth control; abstinence) should be employed for the duration of study 
participation. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 


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22 
 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants who have demonstrated intolerance to 125mg of Palbociclib are ineligible 
for the Phase I portion.   
 
3.2.2 Participants who are receiving any other investigational agents. 
 
3.2.3 Participants who have received previous treatment with an mTOR inhibitor. 
 
3.2.4 Participants who have received prior treatment with exemestane in the metastatic setting 
or who have recurred within 12 months of adjuvant exemestane. 
 
3.2.5 Participants with a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to palbociclib, everolimus or exemestane.  
 
3.2.6 Participants with known brain metastases may be enrolled in this study if radiation 
therapy and/or surgery have been completed with a minimum of 3 months of stable 
disease demonstrated on serial evaluation by CT (with contrast enhancement) or MRI. 
Such participants must no longer require treatment with corticosteroids or enzyme 
inducing anti-epileptic medications for their CNS disease. 
 
3.2.7 Participants with bilateral diffuse lymphangitic carcinomatosis. 
 
3.2.8 Participants with significant symptomatic deterioration of lung function. If clinically 
indicated, pulmonary function tests including measures of predicted lung volumes, DLco, 
O2 saturation at rest on room air should be considered to exclude restrictive pulmonary 
disease, pneumonitis or pulmonary infiltrates. 
 
3.2.9 Evidence of current pneumonitis 
 
3.2.10 Subjects with organ allograft requiring immunosuppression. 
 
3.2.11 Participants with uncontrolled intercurrent illness including, but not limited to: 
• Ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, symptomatic 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; 
• Impairment of gastrointestinal function or who have gastrointestinal disease that 
may significantly alter the absorption of study drugs (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea or malabsorption syndrome). 
 


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23 
3.2.12 Participants receiving any medications or substances that are moderate or strong 
inhibitors or inducers of CYP3A within 7 days of registration. Lists including 
medications and substances known or with the potential to interact with the CYP3A 
isoenzymes are provided in Appendix B, and can also be found within Sections 2.4.1.2 
and 5.8. 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 participant 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 participant is considering a new over-the-counter medicine or herbal 
product. 
 
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. 
 
3.2.13 Pregnant women are excluded. 
 
3.2.14 Individuals with a history of a different malignancy are ineligible except for the 
following circumstances: a) if they have been disease-free for at least 5 years; OR b) are 
deemed by the investigator to be at low risk for recurrence of that malignancy; OR c) if 
diagnosed with the following cancers 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. 
 
3.2.15 Participants known to be HIV-positive on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with palbociclib and 
everolimus. In addition, these individuals are at increased risk of lethal infections when 
treated with marrow-suppressive therapy.  Appropriate studies will be undertaken in 
participants receiving combination antiretroviral therapy when indicated. Screening for 
HIV infection at baseline is not required. 
 
3.3 
Inclusion of Women and Minorities 
 
Women are eligible for this protocol and expected to comprise the majority of participants 
enrolled. Every effort will be made to include participants from minority populations. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 


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24 
OnCore. 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 
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. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
N/A 
4.4 
Registration Process for Other Investigative Sites 
 
N/A 
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
This is a single center, single arm, open label, phase Ib/IIa study of the combination therapy with 
palbociclib, everolimus and exemestane in participants with metastatic HR-positive Her2-negative 
breast cancer. Each subject will be assigned a unique identification number during screening, 
which will be used on all case report forms (CRFs) and correspondence regarding the subject. 
 
Palbociclib will be administered orally, once daily for 21 consecutive days followed by a 7-day 
rest (28-day cycle); everolimus and exemestane will be administered orally, once daily on a 28 
day schedule (Table 5-1). Treatment will be administered on an outpatient basis. Reported adverse 
events and potential risks are described in Section 7. Appropriate dose modifications are described 
in Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the participant's malignancy. 
 
Table 5-1 – Regimen description 
Agent 
Premedication 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Palbociclib 
Not routinely 
necessary 
** 
PO 
Days 1 to 21 
followed by a 
28 days  
(4 weeks) 


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25 
7-day rest 
Everolimus 
Not routinely 
necessary 
** 
PO 
Days 1 to 28 
Exemestane 
Not routinely 
necessary 
25 mg 
PO 
Days 1 to 28 
**Doses as appropriate for assigned dose level 
 
 
Participants will be treated with increasing/decreasing doses of palbociclib and everolimus to 
establish MTD(s)/RP2D for both drugs in the setting of the triple combination of palbociclib, 
everolimus and exemestane. The starting dose level will be palbociclib 100 mg (PO, days 1 – 21 
with 7 days of rest), everolimus 5 mg (PO, daily) and exemestane 25 mg (PO, daily). Only one of 
the two study drugs in the palbociclib-everolimus-exemestane combination can be escalated at a 
time. If participants develop toxicity early in the study, the everolimus dose can be de-escalated 
below the proposed starting dose. If subsequent cohorts of participants tolerate therapy, doses for 
participants on lower dose-levels can then be escalated. However, palbociclib starting doses below 
100 mg will not be explored in this study (Table 5-2).  
 
 
 
Table 5-2 - Provisional dose levels for palbociclib and everolimus for phase Ib 
Dose Escalation Schedule 
Dose Level 
Dose 
Palbociclib 
(mg) 
Everolimus 
(mg) 
Exemestane 
(mg) 
Level -1 
100 
2.5 
25 
Level 0 – Starting dose 
100 
5 
25 
Level 1 
125 
5 
25 
Level 2 
125 
10 
25 
 
The dose for subsequent dose levels will be determined according to the treatment-related adverse 
events observed in the first cycle, as detailed in Table 5-3. Participants must complete a minimum 
of ≥16 doses of palbociclib during within the minimum safety evaluation period (1 cycle, i.e. 28 
days) or have had a DLT within the first cycle of treatment to be considered evaluable for dose 
escalation decisions. The participant will be requested to maintain a medication diary of each dose 
of medication. The medication diary will be returned to clinic staff at the end of each cycle. 
 
Table 5-3 – Escalation decision rules 
Number of Participants with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 


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26 
1 out of 3 
Enter at least 3 more participants at this dose level. 
• If 0 of these 3 additional participants experience DLT, 
proceed to the next dose level. 
• If 1 or more of these additional 3 participants suffer 
DLT, then dose escalation is stopped.  This dose is 
declared the maximally administered dose.  Three (3) 
additional participants will be entered at the next 
lowest dose level if only 3 participants were treated 
previously at that dose. 
>2 out of 3 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose.  Three (3) 
additional participants will be entered at the next lowest 
dose level if only 3 participants were treated previously 
at that dose. 
≤1 out of 6 at highest dose level below 
the maximally administered dose 
This is generally the recommended phase 2 dose. At least 
6 participants must be treated at the recommended phase 
2 dose. 
Dose-limiting toxicity (DLT) for this trial are defined below. Dose escalation will continue until 
identification of the maximum tolerated doses (MTD) or a suitable combination of lower doses for 
Phase II recommended dose (RP2D). 
 
5.2 
Definition of Dose-Limiting Toxicity (DLT)  
 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as having a reasonably possible relationship to the study medication(s) and is unrelated 
to disease, disease progression, inter-current illness, or concomitant medications that occurs within 
the first 28 days of treatment (cycle 1) with palbociclib + everolimus + exemestane and meets any 
of the criteria included in Table 5-4.  The National Cancer Institute Common Terminology Criteria 
for Adverse events (NCI CTCAE) version 4.0 will be used for all grading. Whenever a participant 
experiences toxicity that fulfills the criteria for a DLT, treatment with the study drug combination 
will be interrupted and the toxicity will be followed as described in Section 6. 
 
For the purposes of dose escalation and determination of the MTD(s), DLTs that occur during the 
first cycle will be necessarily considered, including those in which the event started in Cycle 1 but 
confirmation of the DLT occurs in a subsequent cycle. The investigator must notify Pfizer 
immediately of any unexpected CTCAE grade ≥3 adverse events or laboratory abnormalities 
during the DLT period (first 28 days of treatment). Prior to enrolling participants into a higher 
dose level, CTCAE grade ≥2 adverse events will be reviewed for all participants at the current 
dose level.  
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study drug induced adverse events, are provided in Section 6. For 
participants who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the participant to continue the study treatment. These changes must be 
recorded on the CRF.  
 


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Table 5-4 – Study DLT description using the National Cancer Institute Common 
Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 
Toxicity 
DLT criteria 
Hematology   
o CTCAE grade 3 thrombocytopenia 
with bleeding  
o CTCAE Grade 3 or 4 neutropenia with 
fever (temperature ≥38.5°C) 
o CTCAE grade 4 neutropenia lasting 
more than 7 consecutive days  
o CTCAE grade 4 thrombocytopenia  
o CTCAE grade 4 lymphopenia lasting 
more than 7 consecutive days 
Gastro-intestinal   
 
 
o ≥CTCAE grade 3 nausea or vomiting 
≥48 hrs despite optimal anti-emetic 
therapy 
≥CTCAE grade 3 diarrhea ≥48 hrs 
despite optimal anti-diarrhea treatment  
Hepato-biliary  
 
o ≥CTCAE grade 3 total bilirubin 
≥CTCAE grade 3 ALT (isolated 
increases in AST without concomitant 
increases in ALT will not be considered 
dose-limiting, because of the non-
specific nature of AST) or >7.5 x ULN 
for >72 hours in a participant with liver 
metastases 
o ≥CTCAE grade 3 ALT and total 
bilirubin ≥2x ULN (Hy’s Law case) 
where this is felt to be drug-related: 
discontinue study treatment 
 
ECG QT Interval   
 
o QTcF interval ≥501 ms on at least two 
separate ECGs 
Renal 
o CTCAE grade ≥3 serum creatinine  
Other events not described above or listed as 
exceptions to DLT criteria 
o ≥CTCAE grade 3 events 
Exceptions to DLT criteria   
 
 
o < 5 days of CTCAE grade 3 fatigue 
o < 48 hours of CTCAE grade 3 edema  
o Grade 3 laboratory abnormalities that 
are responsive to oral supplementation 
or deemed by the investigator to be 
clinically insignificant 


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5.3 
Definition of maximum tolerated dose (MTD) 
 
The MTD is defined as the highest combination drug dosage not causing medically unacceptable, 
dose-limiting toxicity (DLT) in more than 33% of the treated participants in the first cycle of 
treatment. AEs and laboratory abnormalities considered to be DLTs are defined in Table 5-4. Since 
several combinations may correspond to this definition, more than one MTD may be identified 
with different doses of the combination partners. One of these MTDs or a lower dose combination 
will then be selected as the recommended phase II dose (RP2D). Only one RP2D will be tested in 
the phase II part of the study.  
 
5.4 
Intra-participant dose escalation  
 
Intra-participant dose escalation of palbociclib prior to declaration of MTD(s)/RP2D is not 
permitted with the following exception:  
• Once the MTD(s)/RP2D are/is declared for the palbociclib-everolimus-exemestane 
combination, individual participants may be considered for escalation to treatment at the 
RP2D. In order for a participant to be treated at the RP2D, the participant must have 
tolerated the lower dose combination for at least two cycles of therapy, i.e., the participant 
must not have experienced at the lower dose combination originally assigned a toxicity of 
CTCAE Grade ≥2 for which relationship to study drug cannot be ruled out.  
 
These changes must be recorded on the Dosage Administration Record CRF. 
 
5.5 
Doses for Phase II  
 
The doses of palbociclib-everolimus-exemestane combination are fixed as recommended by the 
Phase Ib part of this study. Only one RP2D will be tested in Phase II. 
 
5.6 
Pre-Treatment Criteria 
 
5.6.1 
Day -21 to Day 1: Screening Visit 
 
Archival tumor samples (when available) will also be requested prior to registration. 
 
Phase II: A baseline tumor biopsy, obtained within prior to starting protocol therapy is also 
required for participants with accessible disease. Further details about collection and handling of 
tumor biopsy specimen can be found in Section 9.1.  
 
5.6.2 
Cycle 1, Day 1 and subsequent cycles 
Participants do not need to re-meet eligibility criteria on Cycle 1 Day 1.  
Treatment criteria for Cycle 1 Day1, subsequent cycles Day 1, and post-treatment interruptions for 
treatment-related toxicity includes:  
• Platelet count ≥ 100,000/mm3; and 
• ANC ≥ 1000/mm3 and no fever; and 
• To resume palbociclib, any grade 3 or higher treatment-related non-hematologic adverse 


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29 
events (AEs) considered related to palbociclib have recovered to Grade ≤ 1 or baseline. To 
resume everolimus, any grade 3 or higher treatment-related non-hematologic adverse 
events (AEs) considered related to everolimus have recovered to Grade ≤ 1 or baseline. AE 
grading criteria can be found online at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
If the retreatment parameters are met within 3 weeks of treatment interruption or cycle delay, 
palbociclib and/or everolimus may be resumed.  Please refer to Dose Reductions Section (Section 
6) for detailed adverse event and dose modifications information 
 
5.7 
Agent Administration 
 
5.7.1 
Palbociclib 
 
Palbociclib should be taken orally, once per day within 1 hour of a meal for 21 consecutive days 
followed by a 7-day rest (28-day cycle). If a dose is vomited, a replacement dose should NOT be 
taken.  If a dose is missed (defined as 4hours from regularly scheduled dose time), it should be 
skipped and NOT retaken.  Participants who inadvertently take 1 extra dose during a day must skip 
the next day’s dose.  Participants should be instructed to swallow the palbociclib capsule whole 
and not to chew, crush or open them. Participants must avoid consumption of grapefruit. 
Participants should be instructed to record daily administration of the study drugs in a drug diary 
(Appendix C). Treatment is continuous daily for 21 days, and then 7 days off, to complete a 28 
day cycle.  
 
In addition, participants will bring pill bottles to visits, and pill counts will be performed as follows: 
• Participants 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 will be 
performed at each study visit.  The number of remaining capsules/tablets will be 
documented and recorded. 
• To be considered evaluable, each study participant must have received at least ≥16 doses 
of palbociclib during the cycle one. 
 
5.7.2 
Everolimus 
 
Everolimus should be taken orally, once per day within 1 hour of a meal. If a dose is vomited, a 
replacement dose should NOT be taken.  If a dose is missed (defined as 4hours from regularly 
scheduled dose time), it should be skipped and NOT made-up. Participants who inadvertently take 
1 extra dose during a day must skip the next day’s dose. Participants should be instructed to 
swallow the everolimus tablet whole and not to chew or crush it. Participants must avoid 
consumption of grapefruit. Participants should be instructed to record daily administration of the 
study drugs in a drug diary (Appendix C). Treatment is continuous daily to complete a 28 day 
cycle. 
 
• Participants will be required to return the completed drug diary at each study visit to assess 
drug adherence. 
 


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30 
5.7.3 
Exemestane 
 
Exemestane should be taken orally, once per day within 1 hour of a meal. If a dose is vomited, a 
replacement dose should NOT be taken.  If a dose is missed (defined as 4hours from regularly 
scheduled dose time), it should be skipped and NOT made-up. Participants who inadvertently take 
1 extra dose during a day must skip the next day’s dose. Participants should be instructed to 
swallow the exemestane tablet whole and not to chew or crush it. Participants should be instructed 
to record daily administration of the study drugs in a drug diary (Appendix C). Treatment is 
continuous daily to complete a 28 day cycle. 
 
In addition, participants will bring pill bottles to visits, and pill counts will be performed as follows: 
• Participants will be required to return all bottles of exemestane as well as the completed 
drug diary at each study visit for drug accountability.  Drug accountability will be 
performed at each study visit prior to dispensing drug supply for the next cycle.  The 
number of remaining capsules/tablets will be documented and recorded. 
• To be considered compliant, each study participant must have received at least 80% of the 
planned number of doses of primary therapy based on the number of days of actual dose 
administration. 
 
5.8 
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 documented in the participant’s medical 
record or research chart.  
 
Supportive care medications are allowed at any time on trial.  Specifically, the following agents 
are permitted: 
• Antiemetics; 
• Antidiarrheal therapy and topical treatments for stomatitis; 
• Antiallergic measures such as corticosteroids and antihistamines. Chronic immunosuppressive 
therapies should be avoided, including systemic corticosteroids.   
• Bisphosphonates: Subjects being treated with bisphosphonates when they enter the study may 
continue the medication as long as the dose is stable. Subjects may also initiate bisphosphonate 
therapy while on protocol therapy if it is thought to be medically necessary. The reason for 
bisphosphonates initiation during after study enrollment must be clearly specified; 
• Agents to assist in management of AI-induced side effects (NSAIDs, gabapentin, duloxetine, 
venlafaxine, citalopram, etc); 
• Pain killers; 
• Packed red blood cells (with the exception of cycle 1); 
• Concurrent metformin is allowable; 
• The use of concurrent investigational or other antitumor therapies, other than everolimus and 
exemestane, is not permitted; 
• The use of any other potential new concomitant medications may be discussed between the 
investigator and the sponsor on a case by case basis. 
 


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31 
Prophylactic myeloid growth factor administration is not permitted for the prevention of 
neutropenia, but is only permitted if clinically indicated in response to a clinically significant 
episode of neutropenia 
 
Participants will be required to tell their treating physican/research nurse about any new 
medications he/she takes after the start of the study drug combination. 
 
Participants taking concomitant medication chronically should be maintained on the same dose 
and dose schedule throughout the study period, as medically feasible. The days of full PK blood 
sampling should be representative of the other study days with regard to the use of the chronically 
administered concomitant medications. However, if a concomitant medication is used 
intermittently during the study, this medication should be avoided on the days of full PK sampling, 
if medically feasible. The use of herbal medicine is not recommended during protocol treatment. 
 
Moderate and 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, aprepitant, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, 
erythromycin, fluconzole, 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, phenobarbital, phenytoin, primidone, rifabutin, rifampin, 
rifapentin, and St. John’s wort, are not allowed in the study.  This medication list may also be 
found in Appendix B. Concomitant use of moderate CYP3A inducers and CYP3A substrates is 
allowable on study, however precaution should be exercised for use of any concomitant 
medication. 
 
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. 
 
Appendix B, palbociclib package insert, and everolimus package insert present information on 
medications/substances that could potentially interact with the study agents. 
 
5.9 
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 event(s), treatment may continue until 
one of the following criteria applies: 


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32 
• 
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 protocol therapy; 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the CRF. Alternative care options will be discussed with the participant. 
 
Additionally the date and reason the patient was removed from protocol therapy will be 
documented in OnCore by the study staff. 
 
5.10 
Duration of Follow Up 
 
Participants who are removed from study therapy for disease progression will be followed for 30 
days or until death, whichever occurs first. 
 
Participants who are alive and free of disease progression at the time of removal from protocol 
therapy will be followed until disease progression or until death, whichever occurs first.  During 
the follow-up period, scans should be performed every 8 weeks +/- 2 weeks (if the participants is 
within 24 weeks of initiation of study treatment) or every 12 weeks +/- 2 weeks (if the participant 
is greater than 24 weeks from initiation of study treatment) to evaluate for disease progression. 
 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
 
5.11 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Progressive Disease for participants removed from protocol therapy for reasons other than 
disease progression 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF) and in OnCore by study staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Sara Tolaney, MD at 617-632-5743 or stolaney@partners.org. 
 


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33 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
If a participant experiences a DLT, then treatment with all drugs must be interrupted (palbociclib, 
everolimus and exemestane). For all toxicity grades and with the exceptions noted from Table 6-
3 to Table 6-11, if the toxicity resolves to grade 1 or baseline within 1 week of onset, treatment 
may be resumed at the same or a lower dose level at the investigator’s discretion and following 
discussion with the overall study PI. If dosing is delayed for toxicities on day 1 of a cycle, the 
cycle start and all assessments will be delayed.  If dosing is interrupted mid-cycle, the next cycle 
and all assessments will stay on schedule. For toxicities that result in treatment delays of more than 
seven but not more than 21 days, treatment may be resumed at a lower dose level. If a participant 
requires a dose interruption of > 21 days from the intended day of the next scheduled dose, then 
the participant must be discontinued from the study. In this event, more frequent follow up may 
be appropriate. All participants will be followed for AEs and for SAEs for 30 days following the 
last dose of study drug.   
 
Dose delays and modifications will be made as indicated in the following tables. 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.  
 
Palbociclib  
 Each participant is allowed a maximum of two dose reductions for palbociclib (Available doses 
in Table 6-1). After this, the participant will be discontinued from the study treatment. For each 
participant, once a dose level reduction for palbociclib has occurred, the dose may not be re-
escalated during subsequent treatment cycles unless approved by the overall study PI. 
 
Table 6-1 – Available dose reductions of palbociclib 
Palbociclib Dose 
125 mg, daily 
100 mg, daily 
75 mg, daily 
Discontinue study treatment 
 
Everolimus 
Management of severe or intolerable adverse reactions may require temporary dose reduction 
and/or interruption of everolimus therapy. If dose reduction is required, the suggested dose is 
approximately 50% lower than the daily dose previously administered.  
 
Available doses of everolimus are presented in Table 6-2. Recommendations for dose reduction, 
interruption or discontinuation of everolimus in the management of adverse reactions are 
summarized from Table 6-3 to Table 6-11. Clinical judgment of the treating physician should guide 
the management plan of each participant based on individual benefit/risk assessment. 
 
Table 6-2 – Available dose reductions of everolimus 
Everolimus Dose 


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34 
10 mg, daily 
5 mg, daily 
2.5 mg daily 
Discontinue study treatment 
 
Exemestane  
No specific dose modifications are recommended for exemestane. Toxicities attributed to 
exemestane should be managed in a manner consistent with the investigator’s usual clinical 
practice. Dose modification guidelines are presented in the following tables: 
 
Table 6-3 – Management of nausea, vomiting and diarrhea with maximal prophylaxis 
Nausea, vomiting and 
diarrhea  
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3 
Withhold palbociclib and/or everolimus until it resolves to ≤ Grade 1. Restart at a 
lower dose. Which drug(s) to hold are left to investigator discretion. 
Grade 4 
Off protocol therapy. 
Recommended management:  antiemetics and antidiarrheal agents. Loperamide antidiarrheal therapy dosage 
schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-free for 12 hours (maximum 
dosage:  16 mg/24 hours); Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Table 6-4 – Management of neutropenia and thrombocytopenia 
Neutropenia and 
thrombocytopenia 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
Grade 1 
No change in dose. 
Grade 2 
No change in dose. 
Grade 3: ANC <1.0 x 
109/L with and without 
fever  
(≥38.5°C) 
Withhold* palbociclib until ANC is ≥1.0 x 109/L and participant is afebrile 
Grade 4: < 500/mm3 or < 
0.5 x 109 /L; without fever 
and/or platelets < 75 x 
109/L 
Withhold* palbociclib until ANC is ≥1.0 x 109/L and the platelet count is ≥75 x 109/L. 
*If treatment delay is ≤7 days, restart at same dose for both. If treatment delay is > 7 days but ≤21 days, restart at 
lower dose of palbociclib. If treatment delay is > 21 days, discontinue study treatment. 
Participants requiring > two dose reductions should go off protocol therapy. 
 
Table 6-5 – Management of non-infectious pneumonitis 
Non-infectious  
pneumonitis 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
Grade 1: Asymptomatic,  
radiographic findings 
only. 
No change in dose. Initiate appropriate monitoring. 
Grade 2: Symptomatic,  
not interfering with ADL 
Continue at assigned dose. 
Consider interruption of therapy. Re-
initiate everolimus at a lower dose.  
 
Rule out infection and consider treatment 


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35 
Non-infectious  
pneumonitis 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
with corticosteroids until symptoms 
improve to ≤grade 1.  
 
Discontinue treatment if failure to recover 
within 4 wks. 
Grade 3: Symptomatic,  
interfering with ADL; O2 
indicated 
Continue at assigned dose. 
Interrupt until symptoms resolve to 
≤Grade 1.  
 
Rule out infection, and consider treatment 
with corticosteroids.  
 
Consider re-initiating everolimus at a 
lower dose. If toxicity recurs at grade 3, 
consider discontinuation. 
Grade 4: Life-
threatening; ventilatory 
support indicated 
Discontinue study treatment, rule out infection, and consider treatment with 
corticosteroids. 
ADL - Activities of daily living. 
 
Table 6-6 – Management of stomatitis 
Stomatitis 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
Grade 1: Minimal 
symptoms,  normal diet 
No dose adjustment required.  
Manage with non-alcoholic mouth wash, salt water (0.9%) mouth wash, or decadron 
mouth rinse several times a day. 
Grade 2: Symptomatic 
but can eat and swallow 
modified diet 
Interrupt palbociclib and everolimus until recovery to grade ≤1.  
Re-initiate both drugs at the same dose. If stomatitis recurs, interrupt dose of both 
drugs until recovery to grade ≤1. Re-initiate both drugs at a lower dose.  
Manage with decadron mouth rinse, topical analgesic mouth treatments (e.g. 
benzocaine, butyl minobenzoate, tetracaine hydrochloride, menthol or phenol) with or 
without topical corticosteroids (i.e. triamcinolone oral paste). 
Grade 3: Symptomatic 
and unable to adequately 
aliment or hydrate orally 
Interrupt palbociclib and everolimus until recovery to grade ≤1.  
Re-initiate both drugs at a reduced dose.  
Manage with topical analgesic mouth treatments (i.e. benzocaine, butyl minobenzoate, 
tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids 
(i.e. triamcinolone oral paste). 
Grade 4: Symptoms 
associated with life-
threatening consequences 
Discontinue everolimus and provide appropriate medical therapy. 
 
 
Table 6-7 – Management of QTc prolongation 
QTc prolongation 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Withhold palbociclib and perform 
frequent ECGs until the QTcF is < 500 
msec. Address electrolyte, calcium and 
magnesium abnormalities. Restart 
palbociclib.  
Continue with assigned dose.  
 


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QTc prolongation 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
 
If findings recur, hold palbociclib until 
resolve to ≤Grade 1, and restart at the next 
lower dose level. If findings recur again, 
discontinue palbociclib. 
Grade 4 
Stop palbociclib, institute emergency care, 
address electrolyte, calcium and 
magnesium abnormalities and perform 
frequent ECGs until the QTcF is < 500 
msec. 
  
Discontinue the participant from the 
study. 
Discontinue the participant from the 
study.  
 
Table 6-8 – Management of metabolic events 
Metabolic events  
(e.g. hyperglycemia,  
dyslipidemia) 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
Grade 1 
No dose adjustment required.  
Initiate appropriate medical therapy and monitor. 
Grade 2 
No dose adjustment required.  
Manage with appropriate medical therapy and monitor. 
Grade 3 
Continue palbociclib at assigned dose. 
Temporary dose interruption of 
everolimus.  
 
Re-initiate everolimus at a lower dose. 
  
Manage with appropriate medical therapy 
and monitor. 
Grade 4 
Continue palbociclib at assigned dose. 
Discontinue everolimus and treat with 
appropriate medical therapy. 
 
Table 6-9 – Management of hepatobiliary toxicity for participants without liver metastases 
Hepatobiliary 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
≥ Grade 3 
Hold everolimus until toxicity improves to ≤Grade 1.  
Restart everolimus at a lower dose for both compounds 
 
 
 
Table 6-10 – Management of hepatobiliary toxicity for participants with liver metastases 
Hepatobiliary 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
>7.5 x ULN for >72 
hours 
Withhold study treatment until toxicity improves to ≤5 × institutional upper limit of 
normal.  
Restart at a lower dose for both compounds 
 


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Table 6-11 – Management of all other toxicities 
All other toxicities 
Management/Next Dose for 
palbociclib 
Management/Next Dose for 
everolimus 
≥ Grade 3 
Determine attribution of toxicity. Hold assigned therapy until resolved to ≤Grade 1 or 
baseline. If treatment delay is >7 days but ≤21 days, restart at lower dose level. If 
treatment delay >21 days, discontinue study treatment. 
 
 
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 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 
Expected toxicities 
 
7.1.1 
Adverse Events for Palbociclib 
 
The primary anticipated toxicity of palbociclib is neutropenia. In the phase I, dose-escalation trial 
of palbociclib alone in advanced cancers88, neutropenia was the only dose-limiting toxicity (DLT).  
Grade 3 neutropenia during cycle 1 was observed in 3/22 participants receiving palbociclib 125 
mg PO daily, with no grade 4 neutropenia 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 participants, 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 participants).  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%).52  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.53,89 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 cancers88, QT interval changes 
were also evaluated in detail.  While 26 of 41 participants had a maximum increase of <30 msec 
from baseline QTc, zero participants had an on-treatment value exceeding 500 msec. 
 
7.1.2 Adverse Events for Everolimus 
 
The following adverse events are considered to be class-effects of mTOR inhibitors: stomatitis/oral 
mucositis/ulcers, infections and infestations, rash and similar events, cytopenia, hemorrhages, non-


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38 
infectious pneumonitis, hyperglycemia/new-onset diabetes mellitus, renal events, and 
thromboembolism. The more common metabolic side effects reported with mTOR inhibitors result 
from inhibitory effects on mTOR-regulated lipid and glucose pathways, while infections stem from 
the immunosuppressive properties of these agents. Virtually all of the side effects associated with 
mTOR inhibitors can be managed effectively with dose modification and/or supportive 
intervention. The safety profile of everolimus observed in the phase III BOLERO-2 study is 
consistent with prior experience in the oncology setting; events are predominantly low grade 
(grade 1 or 2). An increased risk of non-infectious pneumonitis, infection, and stomatitis in the 
everolimus plus exemestane arm relative to the control arm [exemestane + placebo] was observed, 
although each of these events can be effectively managed in this setting. The most common adverse 
events (AEs) suspected to be related to treatment, with an incidence ≥10%, reported in association 
with everolimus plus exemestane therapy were consistent with what was previously reported: 
stomatitis, rash, fatigue, decreased appetite, diarrhea, dysgeusia, nausea, pneumonitis, weight loss, 
anemia, epistaxis, hyperglycemia, thrombocytopenia, and pruritus. The most common grade 3-4 
AEs suspected to be related to treatment with an incidence of ≥2% were: stomatitis, 
hyperglycemia, anemia, pneumonitis, fatigue, elevated alanine and aspartate transaminase 
concentrations, elevated γ-glutamyltransferase concentrations, dyspnea, neutropenia, and 
thrombocytopenia. No new safety concerns have emerged compared to previous experience with 
everolimus monotherapy or combination therapy.  
 
Please refer to the Full Prescribing Information for everolimus for complete safety information: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.   
 
7.1.3 
Adverse Events for Exemestane 
 
The most frequently reported adverse effects for exemestane are gastrointestinal disturbances, hot 
flashes, arthralgia, myalgia, sweating, fatigue, and dizziness. Other reported effects include 
headache, insomnia, somnolence, depression, skin rashes, alopecia, asthenia, and peripheral and 
leg edema. Thrombocytopenia and leukopenia have been reported occasionally. Reductions in 
bone mineral density can occur with long-term use of exemestane. A total of 1058 participants 
were treated with exemestane 25 mg once daily in the clinical trials program. Exemestane was 
generally well tolerated, and adverse events were usually mild to moderate. Adverse events 
occurring in greater than 10% of participants include hot flashes (14%), nausea (11.9%), insomnia, 
headache, increased sweating, joint and musculoskeletal pain, and fatigue (USPI Aromasin SmPC 
August 2008 [UK as RMS for EU MRP]). Androgenic effects were reported in a limited number 
of participants (4.3%).67  
 
Please refer to the Full Prescribing Information for exemestane for complete safety information: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.  
 
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.   


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39 
 
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. 
 
• 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. 
 
• 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 
 
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 will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4 
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. 
 


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40 
7.5 
Expedited Reporting to Pfizer   
 
Within 24 business hours of first awareness of the event 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 the provided Investigator-Initiated Research 
Serious Adverse Event Form (IIR SAE).  The Reportable Event Fax Cover Sheet provided by 
Pfizer must also be included with each SAE submitted.    
    
7.5.1 SAE Definition.    
An SAE is any adverse event, without regard to causality, that is life-threatening (ie, 
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 (ie, 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.    
  
7.5.2 Exposure During Pregnancy, Exposure During Lactation, Occupational Exposure   
Even though there may not be an associated SAE, exposure to the Palbociclib during 
pregnancy, exposure to the Palbociclib during lactation, and occupational exposure to the 
Palbociclib are reportable to Pfizer.    
  
7.5.3 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.  
 
7.5.4 Exclusions from SAE Reporting Requirements  
Specifically excluded from the reporting requirements is any SAE judged by the Overall 
Investigator to represent progression of the malignancy under study, unless it results in 
death within the SAE Reporting Period.    
  
7.5.5 SAE Reporting Period  
 


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41 
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.   
 
7.6 
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 Grade 2 or greater 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 or other 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-
N 
N 
N 
O
H N 
N 
N 
N 
C H 3 
O
C H 3
H


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42 
ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one 
Chemical formula: C24H29N7O2 
Molecular weight: 447.53 
Half life: ~27 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 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. 
Information on potential drug interactions can be found in Appendix B.   
 
8.1.2 
Form 
 
Palbociclib will be supplied by Pfizer from commerical supply 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 8-1 – Palbociclib capsule characteristics 
Dosage 
Capsule color 
Capsule size 
75 mg 
Sunset Yellow/Sunset Yellow 
2 
100 mg  
Caramel/Sunset Yellow 
1 
125 mg 
Caramel/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 both the 
room storage and refrigerator 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 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 


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43 
needs to be dispensed. 
 
8.1.4 
Compatibility 
 
No compatibility issues are known for co-administration of palbociclib and everolimus or 
exemestane. 
 
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 supplied free-of-charge from Pfizer. 
 
8.1.7 
Administration 
 
Palbociclib will be provided in non-participant-specific bottles containing 75 mg, 100 mg or 
125 mg capsules.  
The medical record number should be recorded on the bottle label in the spaces provided by site 
personnel at the time of assignment to participant.  Site personnel must ensure that participants 
clearly understand the directions for self-medication.  Participants 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 
participants.  
Palbociclib is an agent that must be handled and administered with care.  Participants 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 participant at each dispensing visit.  In the 
event of dose modification, request should be made of the participant to return all previously 
dispensed medication to the clinic and new capsules will be dispensed. 
 
8.1.8 
Ordering 
 
Palbociclib will be provided to the Institutional pharmacy by Pfizer.  
 
8.1.9 
Accountability 
 


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To ensure adequate records, palbociclib capsules will be accounted for as instructed by Pfizer.  
Participants 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, is responsible for 
maintaining 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.) 
 
8.1.10 Destruction and Return 
 
Any undispensed/unopened investigational drug will be returned to the sponsor or destroyed 
onsite per institutional guidelines following the completion of research drug dosing by the last 
subject on the protocol. A member of the research team should notify the research pharmacy at all 
sites at which the trial is being conducted when the last subject on the protocol at that site has 
completed research drug dosing.  
 
Returned supply by a participant will be destroyed per institutional guidelines following 
reconciliation by the pharmacy staff.  
 
 
8.2 
Everolimus 
 
8.2.1 
Description 
 
 
 
 
Chemical 
name: 
dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-
methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-
hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0 
hexatriaconta-16,24,26,28-
tetraene-2,3,10,14,20-pentone 


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45 
Chemical formula: C53H83NO14 
Molecular weight: 958.224 
Half life: ~30 hours 
Plasma protein binding of everolimus: ~74% 
 
Everolimus is extensively metabolized in the liver via CYP3A4; forms 6 weak metabolites. 
Information on potential drug interactions can be found in Appendix B. 
 
8.2.2 
Form 
 
Everolimus is commercially available as 2.5mg, 5mg, and 10 mg tablets.  
8.2.3 
Storage and Stability 
 
Everolimus should be stored according to the package insert. 
 
8.2.4 
Compatibility 
 
Everolimus was shown to increase exposure of exemestane. No compatibility issues are known 
for co-administration of everolimus and palbociclib. 
 
8.2.5 
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.  
 
8.2.6 
Availability 
 
Everolimus is commercially available as Afinitor®.  
 
8.2.7 
Administration 
 
Everolimus will be dispensed in non-participant-specific bottles containing 2.5 mg, 5 mg or 10 mg 
tablets.  
 
8.2.8 
Ordering 
 
Everolimus is commercially available. 
 
8.2.9 
Accountability 
 
The investigator or designee will comply with all institutional commercial drug SOPs. 
 


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46 
8.2.10 Destruction and Return 
 
N/A 
 
8.3 
Exemestane 
 
8.3.1 
Description 
 
 
 
Chemical name: 6-Methylideneandrosta-1,4-diene-3,17-dione 
Chemical formula: C20H24O2 
Molecular weight: 296.403 
Half life: ~24 hours 
Plasma protein binding of palbociclib: ~90% 
 
In vitro, exemestane is primarily metabolized by CYP3A4 enzymes. Information on potential drug 
interactions can be found in Appendix B.   
 
8.3.2 
Form 
 
Exemestane is commercially available as 25 mg of exemestane.  
8.3.3 
Storage and Stability 
 
Storage conditions stated in the Single Reference Safety Document (i.e., United States Package 
Insert (USPI), Summary of Product Characteristics (SPC), or Local Product Document (LPD)) 
will be superseded by the label storage. 
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 both the 
room storage and refrigerator storage.  Any temperature excursions must be reported to the overall 
study PI.  The investigational products must be stored as indicated.  Deviations from the storage 


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47 
requirements, including any actions taken, must be documented and reported to the overall study 
PI.   
Once a deviation is identified, the investigational products must be quarantined and not used until 
the overall study PI 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. 
 
8.3.4 
Compatibility 
 
Everolimus (that is given in the same regimen) was shown to increase exposure of exemestane. 
No other compatibility issues are known for co-administration with everolimus and palbociclib. 
 
8.3.5 
Handling 
 
Only qualified personnel, familiar with institutional procedures should handle the agent.  
 
8.3.6 
Availability 
 
Exemestane will be from commerical supply.  
 
8.3.7 
Administration 
 
Exemestane will be provided in non-participant-specific bottles containing 25 mg tablets.  
The participant number should be recorded on the bottle label in the spaces provided by site 
personnel at the time of assignment to participant.  Site personnel must ensure that participants 
clearly understand the directions for self-medication.  Participants 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 
participants.  
Exemestane is an agent that must be handled and administered with care.  Participants 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, tablets must not be broken and must be swallowed intact. 
8.3.8 
Ordering 
 
Exemestane will be provided to the Institutional Pharmacy by Pfizer.  
 
8.3.9 
Accountability 
 
To ensure adequate records, exemestane tablets will be accounted for as instructed by Pfizer.  
Participants are requested to return previously dispensed containers as well as their completed drug 


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48 
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.) 
 
8.3.10 Destruction and Return 
 
At the end of the trial, exemestane will be destroyed and documented as per institutional policies.  
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
cfDNA Collection 
For a number of reasons that include discomfort to the participant, logistical challenges, and lack 
of clinical indication, serial biopsies in individual participants in the metastatic setting are 
infrequently performed.  It has therefore been challenging to study the molecular evolution of 
tumors over time and through progression on serial treatment regimens. However, emerging 
technology now permits whole exome sequencing from cell-free DNA (cfDNA) isolated from 
fresh blood. We aim to examine the utility of this approach for detecting molecular changes in 
individual participants’ tumor cell populations over time by performing serial cfDNA. 
 
9.1.1 
Objectives 
 
• To collect blood specimens to characterize tumors, and bank for future studies 
including molecular evaluations of disease characteristics, genetic variability, and 
immunological function.  
 
9.1.2 
Specimen Collection and Handling 
For cfDNA analyses, two 10 mL blood samples will be drawn into EDTA-containing 
“purple top” test tubes or Streck Tubes. Blood will be collected at baseline, restaging 
visits, and at time of progression/off study. Within two hours the cfDNA will be 
processed and banked in the DF/HCC Clinical Trials Core laboratory for future research 
purposes. 
 
Given the time sensitive nature of processing these samples, please email the DF/HCC 
Clinical Trials Core laboratory (dfcibreastbank@partners.org) with the patient name, 
study ID, date of collection, approximate time of collection and study time point the day 
prior to collection.  
 
It is anticipated that future studies will include evaluation of genetic, immunologic, 
hormonal, and/or other issues related to breast cancer.  We will inform participants in the 
informed consent document that we will use their specimens for research related to breast 


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49 
cancer and other cancers.   
 
Throughout the length of the trial, cfDNA plasma samples will be batch shipped to the 
Broad Institute under the direction of Nikhil Wagle, MD for sequencing on the Institute’s 
Genomic Platform.  
 
9.1.3 
Sites  
 
Dana-Farber Cancer Institute 
The Broad Institute 
 
 
9.2 
Exome Analysis 
9.2.1 
Objectives 
• To complete pharmacogenomic analyses related to drug response or adverse drug 
reactions  
• To collect and perform germline exome sequencing as a control for the paired 
tumor biopsies.  
 
9.2.2 
Specimen Collection 
 
One 10mL purple top tube should be collected at Cycle 1 Day 1.  
 
9.2.3 
Specimen Handling/Shipping 
 
The purple top tube will be brought/sent on the day of collection to: 
 
 
 
The Wagle Lab 
 
Nikhil Wagle, MD 
 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue 
 
Boston, MA 02215 
 
Throughout the length of the trial, these samples will be batch shipped to the Broad 
Institute for sequencing under the direction of Nikhil Wagle, MD.  
 
 
9.2.4 
Sites  
Dana-Farber  
The Broad Institute  
 
9.3 
Pharmacokinetic Studies 
Sampling will be performed in all patients enrolled to the Phase I portion to define the whole 
blood concentration-time profile of everolimus over a single 24 hour dosing interval for the 
initial dose given on day 1and for the dose given on day 15 of cycle 1.  Additional samples will 
be collected at each of the same times relative to the dose given on day 15 to define the plasma 
concentration-time profiles for exemestane and palbociclib.  The sampling schedule has been 
devised to accommodate treatment on an outpatient basis.   


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50 
 
Blood samples will be obtained from a peripheral arm vein shortly before dosing on days 1 and 
15 and then at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 h after dosing.  The 24.0 samples must be 
collected before the next daily doses of the three drugs are taken on days 2 and 16.  It is very 
important that the patient is aware that the morning doses of all three drugs on days 2 and 16 
must not be taken before arriving at the clinic and the 24.0 h pharmacokinetic samples have been 
collected.   
 
The Vacutainer tubes used to collect the pharmacokinetic samples are as follows: 
 
• Everolimus:  2 mL green top sodium heparin Vacutainer tube (Becton Dickinson cat. # 
367671) 
• Exemestane:  6 mL green top sodium heparin Vacutainer tube (Becton Dickinson cat. # 
367878) 
• Palbociclib:  4 mL lavender top K2EDTA Vacutainer tube (Becton Dickinson cat. # 
367861) 
 
Blood samples will be collected in all three types of collection tubes prior to giving the initial 
dose on day 1.  Blood samples will only be collected in the 2 mL green top Vacutainer tubes for 
the 7 time points after dosing on day 1 and day 2 (24 hours after the day 1 dose, before the day 2 
dose).  Blood samples will be collected in all three tubes shortly before dosing on day 15 and at 
each of the 7 time points after dosing on day 15 and day 16 (24 hours after the day 15 dose, 
before the day 16 dose).  The total volume of blood collected for pharmacokinetic studies will be 
122 mL over a time interval of 16 days.   
 
A Laboratory Manual will be prepared by the DF/HCC Cancer Pharmacology Core with detailed 
instructions for sample collection and handling, processing the samples for storage, storage 
conditions, packaging, and shipment.  In addition, the Core will prepare a Pharmacokinetic 
Dosing and Sample Collection Time Form and a template for printing labels for the blood 
collections tubes and sample transport vials.  These materials will be made available to the study 
sites in advance enrolling patients into the study.   
 
9.4 
Tissue Collection: The molecular underpinnings of CDK 4/6 inhibitors response and resistance 
 
A baseline research biopsy prior to study therapy initiation is required in the phase IIa part of this 
study, and optional in the phase Ib part.  Additionally, a second research biopsy will be requested 
at the time of disease progression in the case that participants have not started on a new treatment 
regimen. We plan to use this paired information to perform a number of studies characterizing 
disease response and resistance to therapy. Background information on the rationale for these 
investigations is discussed in Section 2.6.  Paired evaluations at the DNA, RNA and protein levels, 
respectively by whole exome sequencing, RNA Seq and immunohistochemistry will be performed. 
Moreover, we will bank specimens for possible future studies. 
 
 
9.4.1 
Objectives 
 


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51 
To characterize the landscape of genomic changes to provide insight about determinants of 
response and resistance to CDK 4/6 inhibitors. To seek for IHC correlates of genomic changes. To 
bank samples for future studies, including molecular evaluations of disease characteristics, genetic 
variability and immunological function.  
 
9.4.2 
Hypothesis 
 
We hypothesize that molecular analysis of tumor samples at baseline and at disease progression 
will allow for the identification of molecular determinants of response and resistance to CDK 4/6 
inhibitors, namely concerning p16-cyclin D/CDK-Rb-E2F and p53 pathways aberrations. We 
further hypothesize that some of these findings can be assessed using IHC techniques. 
 
9.4.3 
Collection, Handling and Shipping of Specimens 
 
Tissue specimens will be collected from metastatic lesions using standard institutional procedures. 
Core biopsies are required and fine needle aspirates cannot be used. All samples will be 
anonymized by assigning a unique sample ID number prior to use. 
 
Following research biopsy of a specimen, 1 tissue core will be placed in formalin and sent to the 
pathology department at BWH for H&E staining, IHC for receptor testing as well as specific Rb 
pathway investigation under Dr. Stuart Schnitt’s supervision. The other cores will be frozen in 
OCT and sent to the lab of Dr Nikhil Wagle at the Dana-Farber Cancer Institute/Broad Institute of 
Harvard and MIT for whole exome/transcriptome sequencing. The tissue not used will be stored 
for future research.  
 
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 participant 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. 


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52 
• 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. 
 
Of note, the above indications 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 participant 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 participant 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, in which case, the participant would not be required 
to undergo a separate research biopsy for entry into this protocol. 
 
If a participant has more than one site of disease, only one site needs to be biopsied, and the site is 
left to the discretion of the participant and her treating physician. Participants 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.  
 
For archival tissue collection, tissue blocks of primary and/or metastatic tumor samples should be 
sent to Dana-Farber Cancer Institute. If blocks cannot be submitted, 20 unstained slides are 
acceptable.  
 
9.4.4 
Site(s) Performing Correlative Study 
Dana-Farber Cancer Institute 
Brigham and Women’s Hospital 
The Broad Institute 
 
 
9.4.5 
Tissue banking 
 
All leftover tissue will be banked in the Dana-Farber Cancer Institute Breast Cancer Tissue Bank 
under the supervision of Dr. Deborah A. Dillon as per standard lab protocol, such that it can be 
used for additional or future analyses as needed. 
 
9.4.6 
Additional Analysis 
 


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53 
The above-mentioned analyses may be altered based on novel developments in the field of 
genomic analysis at the time of correlative science.  Additional markers or alternative technologies 
(based on scientific developments and/or novel technologies) may also be used, to explore 
potential prognostic or predictive candidate markers/panels or markers related to treatment benefit 
and/or safety, to improve diagnostic tests, or to understand breast cancer biology. 
 
 
10. STUDY CALENDAR 
 
Table 10-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. Assessments must be performed prior to administration of any study agent. During the 
escalation portion of the study, there will be a +1 day window during the first cycle; however, 
there is no window permitted on days that require PK sampling.  After the first cycle of the 
escalation portion and during the expansion, study assessments and agents should be administered 
within + 3 days of the protocol-specified date, unless otherwise noted. Laboratory assessments that 
were completed within 3 days prior to Day 1 of each cycle (e.g. cycle 1, day 1) do not need to be 
repeated. For efficacy assessments there is a ±7 days window. Baseline evaluations are to be 
conducted within 21 days (14 days for labs) week prior to start of protocol therapy.  Screening 
CT/MRI scans and pre-treatment tumor biopsy must be completed within 28 days before the first 
dose of study treatment. 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. 


54 
 
Table 10-1 – Study calendar 
 
Screening 
Treatment phase 
End of therapy 
30 Day F/U 
Disease 
Progression F/U 
 
Cycle 1 
Cycle 2 
 
Subsequent 
cycles 
Day of cycle 
-28 to -1 
1 
2 
8 
15 
16 
22 
1 
15 
1 
≤14 days after 
decision to 
discontinue 
 
Phase II only 
Informed consent/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion /exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history/prior 
cancer history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Physical exama 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Performance status 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
Single, 12-lead ECG 
X 
 
 
Xc 
 
 
 
X 
 
 
 
 
 
Blood 
collection 
Hematology 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Chemistryd 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Fasting glucose 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PK Sampling Phase Ibe 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
cfDNA Collection 
 
X 
 
 
 
 
 
 
 
Xi 
Xi 
Xi 
Xi 
Exome Sequencing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
CT/MRI tumor assessment 
X 
 
 
 
 
 
 
 
 
Xf 
X 
 
Xg 
Bone scan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Research tumor biopsy  
Xj 
 
 
 
 
 
 
 
 
 
 
Xh, j 
Xh, j 
 
 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
55 
 
Screening 
Treatment phase 
End of therapy 
30 Day F/U 
Disease 
Progression F/U 
 
Cycle 1 
Cycle 2 
Subsequent 
cycles 
 
 
Day of cycle 
-28 to -1 
1 
2 
8 
15 
16 
22 
1 
15 
 
≤14 days after 
decision to 
discontinue 
1 
Phase II only 
Archival tumor sample  
(Phase IIa part only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Antineoplastic therapies since 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Phone calls for disease progression F/U 
evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a. 
A complete physical examination that evaluates all major organ systems will be performed at Screening/baseline. Subsequent physical exams may be limited and should be focused on 
sites of disease to explore clinical signs and symptoms. 
b. 
Vital signs to include: diastolic and systolic blood pressure, heart rate, temperature, and weight 
c. 
 ECG on C1D8 is only required for participants enrolled in the phase Ib part of the study. 
d. 
Chemistries to include: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], 
and sodium. 
e. 
PK samples will be collected on days 1 and 15 immediately before dosing and at 30min, 1hr, 2hr, 4hr, 6hr, and 8hr after dosing with a +/- 5 minute window allowed for each time 
point. The  24hr PK samples will be collected within a +/- 60minute window on days 2 and 16 prior to dosing. 
f. 
Radiologic measurements should be performed every 8 weeks. Tumor evaluations will be performed within days prior to Day 1 of cycles 3, 5 and 7. Subsequent evaluations will be 
performed within 7 days prior to day 1 of every 4th cycle, or sooner if there is clinical evidence of disease progression. Radiologic documentation must be provided for participants 
removed from study for progressive disease. 
g. 
Tumor evaluations and follow-up will be performed every 8 weeks (if the participants is within 24 weeks of initiation of study treatment) or every 12 weeks (if the participant is 
greater than 24 weeks from initiation of study treatment); time counting since last tumor evaluation and performed within ±2 weeks. 
h. 
Performed at within 30 days of disease progression and prior to participant initiating another anti-tumor treatment. 
i. 
Sample collected for cfDNA at baseline, each restaging visit, end of study, and time of disease progression. 
j. 
Baseline research biopsy is required for participants enrolled to the Phase II portion and optional for patients enrolled to the Phase I portion.  A research biopsy is optional at time of 
progression for Phase Iband Phase II participants.  
k. 
Urine pregnancy test required for participants that are premenopausal and are on a GnRH agonist. 


56 
 
11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of the phase Ib part of this trial, participants with 
measurable disease will be assessed by standard criteria. As for the phase IIa part, the measure of 
efficacy will be CBR, defined as the proportion of participants with complete response, partial 
response or stable disease for more than 6 months.  
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks.  
After the end of therapy visit, tumor evaluations will be performed every 8 weeks (if the 
participants are within 24 weeks of initiation of study treatment) or every 12 weeks (if the 
participant is greater than 24 weeks from initiation of study treatment). In addition to a baseline 
scan, confirmatory scans should also be obtained 4 weeks following initial documentation of 
objective response. 
 
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 Target Disease 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.  
(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.  
 
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). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. Overall, such lesions will not be considered measurable in this 
study. 
 
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 


DF/HCC Protocol #: 16-177 
Protocol Version Date: October 18, 2017 
 
57 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
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. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 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 unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 


DF/HCC Protocol #: 16-177 
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58 
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.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 


DF/HCC Protocol #: 16-177 
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59 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed.   
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained.  
Participant preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days total). 
For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops t.i.d., and 
for adults 3 drops t.i.d. Participants and/or parents are asked about exposure to potential 
interfering agents. If none is noted, an indwelling intravenous line is established. The 
dose of MIBG is administered by slow intravenous injection over 90 seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A large 
field of view dual head gamma camera with low energy collimators is preferred.  
 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later data and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure from 
CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 


DF/HCC Protocol #: 16-177 
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60 
 
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 participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-
125 progression criteria which are to be integrated with objective tumor assessment for use 
in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
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. 
 
11.1.3.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one 
or more new lesions is also considered progressions). 
 
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. 
 
11.1.3.2 
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 participant to be considered in complete clinical response. 
 
Non-CR/Non-PD:  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 and/or unequivocal 


DF/HCC Protocol #: 16-177 
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61 
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.     
 
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). 
 
11.1.3.3 
Evaluation of New Lesions 
 
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 (for example, some ‘new’ bone lesions may be simply 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. 
 
11.1.3.4 
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 participant'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. 
 


DF/HCC Protocol #: 16-177 
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62 
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. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.4 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.  
 
11.1.5 Clinical benefit rate 
 
Clinical Benefit Rate: Clinical Benefit Rate (CBR) is defined as the proportion of 
participants achieving complete response, partial response or stable disease for more than 
6 months taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements. 
 
11.1.6 Progression-Free Survival 
 
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. 
 


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63 
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 responses will be reviewed by an expert, independent of the study, at the study’s 
completion with simultaneous review of the participants’ files and radiological images.  
 
 
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 ODQ will collect, manage, and perform quality checks on the data for this study. 
 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
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 
Multicenter Guidelines 
 
N/A. 
 
12.4 
Collaborative Agreements Language 
 
N/A. 


DF/HCC Protocol #: 16-177 
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64 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a single center, single arm, open-label, phase Ib/ IIa study. We will include participants 
with ER+/Her2− advanced breast cancer that progressed on a CDK 4/6 inhibitor regimen and a 
NSAI for the treatment with palbociclib plus everolimus plus exemestane. Participants will be 
accrued in a single-stage fashion. For the phase Ib part of the study, after registration, participants 
will proceed in independent groups for dose-escalation using a classic 3+3 rule. Dose levels are 
detailed in Table 5-2 and escalation will proceed as detailed in Table 5-3.  
 
Table 13-1 – Operating characteristics of the 3+3 dose escalation design under different true 
rates of dose limiting toxicity (DLT). 
 
 
 
Dose Escalation using 3+3 rule 
True DLT rate 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
Probability 
91% 
71% 
49% 
31% 
17% 
8% 
3% 
 
For the phase IIa of the study, participants will be enrolled using the MTD or RP2D obtained from 
phase Ib part. Two research biopsies are required over the course of study (collection is not 
mandatory during phase Ib): one at pre-treatment baseline (biopsy 1) and a second at disease 
progression (biopsy 2).  
 
Toxicity will be graded and reported as per NCI CTCAE version 4.03. All participants who receive 
any amount of the study drug will be evaluable for toxicity. DLTs are defined in Section 5.2 and 
listed in Table 5-4. MTD is defined in section 5.3 and either the MTD or the maximum dose of 
palbociclib 125 mg plus everolimus 10 mg plus exemestane 25 mg will be the doses used for 
further testing in phase IIa part of the study. 
 
Primary endpoints: 
 
• Phase Ib part: To describe safety, tolerability and MTD/RP2D of the combination of 
palbociclib plus everolimus plus exemestane; 
• Phase IIa part: To estimate efficacy, as defined by CBR, of the combination of palbociclib 
plus everolimus plus exemestane. 
 
Secondary endpoints: 
 
Secondary clinical endpoints 
• Phase IIa part: To estimate the activity of the combination of palbociclib plus everolimus 
plus exemestane, as defined by overall response rate (ORR), disease control rate (DCR), 
duration of response (DOR) and progression free-survival (PFS) according to investigator 
assessment; 
• To describe the PK profile of everolimus and palbociclib in the triple combination and 
evaluate the DDI potential (effect of palbociclib on the PK profile of everolimus). 
 


DF/HCC Protocol #: 16-177 
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65 
Correlative science endpoints 
• To investigate biomarkers of sensitivity and resistance to CDK 4/6 inhibitors via whole 
exome analysis and RNA Seq of paired tumor biopsies; 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
Phase IIa study part 
A total of 32 participants will be accrued within two and a half years. Up to an additional 6 months 
of follow-up will be required on the last participant accrued to observe the participant’s response 
after the 6th cycle of protocol therapy, for a total study duration of 3 years. 
 
In this study participants will receive the triplet combination of palbociclib plus everolimus and 
exemestane after progression to a CDK4/6 inhibitor regimen and to an NSAI. Despite the fact that 
palbociclib was not available at the time of the approval of the combination of everolimus plus 
exemestane (BOLERO-219,90), everolimus plus exemestane is still considered a standard regimen 
in this setting. Using this combination, the observed CBR (as per central assessment) was of 49.9% 
in the everolimus + exemestane arm and of 22.2% in the exemestane plus placebo arm.90 Provided 
that in the population of the current trial participants were further exposed to a CDK4/6 inhibitor 
regimen, we estimate that the true CBR in this population with the treatment with everolimus plus 
exemestane is of 40%. Therefore, we will use 40% as the estimated true CBR. We consider that a 
CBR equal or superior to 65% with the combination of palbociclib plus everolimus and 
exemestane would be worthy of further study. 
 
Table 13-2 – Sample size using the exact binomial method as a function of one sided alpha and 
power. 
One-sided 
alpha 
Power 
Sample size 
min # of 
positive to 
reject null 
Exact alpha 
0.1 
80% 
19 
11 
0.09 
0.1 
90% 
29 
16 
0.07 
0.05 
80% 
28 
16 
0.05 
0.05 
90% 
34 
19 
0.04 
Note: Exact binomial method was used with a one-sided alpha of 0.1 and type II error of 0.1 (90% 
power).  The study needs to enroll 29 evaluable participants to test CBR 65% against a null 
hypothesis of 40% (exact alpha=0.07).  In this setting, if at least 16 out of 29 participants have 
clinical benefit, the regimen is worthy further investigation. Admitting a 10% drop out rate, we 
will recruit 32 participants. 
 
Mandatory biopsies for correlative studies 
We anticipate that 90% of pairs of tumor specimens will be evaluable for resistance mutation.  
Mutation seen in pre- and post-treatment samples will be summarized using contingency tables. 
With 26 pairs of pre- and post-treatment samples, there are 41% and 74% probabilities of observing 
at least one resistance mutation if the true frequency of resistance mutation is 2% and 5%, 
respectively; and 90% power to detect 25% resistance mutation (e.g. mutation prevalence increases 
from 5% to 30% or from 25% to 50% relative to pre-treatment samples), assuming that 1% of 
participants unexpectedly show mutations in only the pre-treatment biopsy (Table 13-2; 


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66 
McNemar’s test, one-sided α=0.1). 
 
Table 13-3 – Sample size using McNemar’s method as a function of one sided alpha and power. 
Total 
participants 
enrolled 
Paired  
samples 
evaluable 
for mutation 
Prob. of obs. at least 
one resistance 
mutation if freq. is 
2% 
Prob. of obs. at least 
one resistance 
mutation if freq. is 
5% 
Min. detectable 
change in 
prevalence of 
mutation post-
treatment 
19 
17 
29% 
58% 
36% 
29 
26 
41% 
74% 
25% 
28 
25 
40% 
72% 
26% 
34 
30 
45% 
79% 
22% 
Note: McNemar’s test with one sided alpha of 0.1 and type II error of 0.1 (90% power) was used 
to calculate the minimal detectable change in prevalence of mutation post-treatment, assuming that 
1% of participants unexpectedly show mutations in only the pre-treatment biopsy. 
 
13.3 
Stratification Factors 
 
No stratifications or interim monitoring determinations will be performed. 
 
13.4 
Interim Monitoring Plan 
 
N/A. 
 
13.5 
Analysis of Primary Endpoints 
 
Phase Ib 
The determination of the MTD under the dose de-escalation scheme is defined in Table 5-3.  
Treatment-related toxicities will be summarized by maximum grade and by term using CTCAE 
v4.0 and reported with 90% binomial exact confidence intervals.  
 
Phase IIa 
CBR is defined in Section 11. The primary endpoint will be analyzed in all the participants eligible 
for the phase IIa part of the study. Descriptive statistics will be used to summarize CBR 
(proportion). The 95% CI will also be calculated for the proportion of participants reaching the 
definition of CBR. We consider that a CBR equal or superior to 65% with the combination of 
palbociclib plus everolimus and exemestane would be worthy of further study. 
 
13.6 
Analysis of Secondary Endpoints 
 
Overall response rate (ORR), disease control rate (DCR) and duration of response (DOR) are 
defined in Section 11. Response will be assessed among participants eligible for the phase IIa part 
of the study who received at least one dose of the study drugs at the MTD/RP2D and have 
measurable disease at screening. Radiographic response will be assessed using RECIST 1.1 criteria 
as defined in section Section 11. The ORR, DCR and DOR will be reported with 95% confidence 
intervals.   
 


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67 
Progression free-survival (PFS) is defined in Section 11. PFS will be described using the method 
of Kaplan-Meier, and it will be presented with a 95% confidence interval. Participants alive 
without disease progression are censored at the date of last disease evaluation. 
 
Correlative objectives will be presented as descriptive statistics, using summary statistics (such as 
mean, SD, median, IQR and range). Correlation to responses will be reported as odds-ratios with 
95% confidence intervals.  Specifically, we plan to measure Rb and p53 status by 
immunohistochemistry in baseline biopsies, and correlate baseline Rb and p53 status with response 
(by RECIST) as an exploratory analysis. 
 
 
13.7 
Reporting and Exclusions 
 
13.7.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. Participants 
who never start protocol therapy will be considered inevaluable. 
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
Analyses will be performed as intent-to-treat and restrict to those participants eligible for the phase 
IIa part of the study. Participants who never start protocol therapy will be considered inevaluable. 
 
 
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. The Primary Investigator will be the final arbiter of the manuscript 
content.    
 
 
 


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phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen 
receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406-13. 
doi:10.1172/JCI41680. 
73.  
Herrera-Abreu MT, Asghar US, Elliot R, et al. Abstract 86O: PI3 kinase/mTOR inhibition 
increases sensitivity of ER positive breast cancers to CDK4/6 inhibition by blocking cell 
cycle re-entry driven by cyclinD1 and inducing apoptosis. Ann Oncol. 2015;26(suppl 
3):iii29-iii29. doi:10.1093/annonc/mdv120.01. 
74.  
Vora SR, Juric D, Kim N, et al. CDK 4/6 Inhibitors Sensitize PIK3CA Mutant Breast 
Cancer to PI3K Inhibitors. Cancer Cell. 2014;26(1):136-149. 
doi:10.1016/j.ccr.2014.05.020. 
75.  
Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a 
therapeutic target in cancer. Nat Rev Cancer. 2011;11(8):558-572. doi:10.1038/nrc3090. 
76.  
Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor-Positive Advanced 
Breast Cancer. N Engl J Med. 2015;373(3):209-19. doi:10.1056/NEJMoa1505270. 
77.  
Gauthier ML, Berman HK, Miller C, et al. Abrogated response to cellular stress identifies 
DCIS associated with subsequent tumor events and defines basal-like breast tumors. 
Cancer Cell. 2007;12(5):479-91. doi:10.1016/j.ccr.2007.10.017. 
78.  
Lukas J, Bartkova J, Rohde M, Strauss M, Bartek J. Cyclin D1 is dispensable for G1 
control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol Cell 
Biol. 1995;15(5):2600-11. Available at: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=230490&tool=pmcentrez&ren
dertype=abstract. Accessed May 17, 2015. 
79.  
Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 
inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 
2010;29(28):4018-32. doi:10.1038/onc.2010.154. 
80.  
Ewen ME, Oliver CJ, Sluss HK, Miller SJ, Peeper DS. p53-dependent repression of 
CDK4 translation in TGF-beta-induced G1 cell-cycle arrest. Genes Dev. 1995;9(2):204-
217. doi:10.1101/gad.9.2.204. 
81.  
Miller SJ, Suthiphongchai T, Zambetti GP, Ewen ME. p53 Binds Selectively to the 5’ 
Untranslated Region of cdk4, an RNA Element Necessary and Sufficient for Transforming 
Growth Factor beta - and p53-Mediated Translational Inhibition of cdk4. Mol Cell Biol. 
2000;20(22):8420-8431. doi:10.1128/MCB.20.22.8420-8431.2000. 
82.  
Konecny GE, Winterhoff B, Kolarova T, et al. Expression of p16 and retinoblastoma 
determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res. 
2011;17(6):1591-602. doi:10.1158/1078-0432.CCR-10-2307. 


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Protocol Version Date: October 18, 2017 
 
75 
83.  
Barton KL, Misuraca K, Cordero F, et al. PD-0332991, a CDK4/6 inhibitor, significantly 
prolongs survival in a genetically engineered mouse model of brainstem glioma. PLoS 
One. 2013;8(10):e77639. doi:10.1371/journal.pone.0077639. 
84.  
Wagle N, Grabiner BC, Van Allen EM, et al. Response and Acquired Resistance to 
Everolimus in Anaplastic Thyroid Cancer. N Engl J Med. 2014;371(15):1426-1433. 
doi:10.1056/NEJMoa1403352. 
85.  
Wagle N, Van Allen EM, Treacy DJ, et al. MAP kinase pathway alterations in BRAF-
mutant melanoma participants with acquired resistance to combined RAF/MEK inhibition. 
Cancer Discov. 2014;4(1):61-8. doi:10.1158/2159-8290.CD-13-0631. 
86.  
Van Allen EM, Wagle N, Sucker A, et al. The genetic landscape of clinical resistance to 
RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4(1):94-109. 
doi:10.1158/2159-8290.cd-13-0617. 
87.  
Wagle N, Emery C, Berger MF, et al. Dissecting therapeutic resistance to RAF inhibition 
in melanoma by tumor genomic profiling. J Clin Oncol. 2011;29(22):3085-3096. 
doi:10.1200/JCO.2010.33.2312. 
88.  
Flaherty KT, Lorusso PM, Demichele A, et al. Phase I, dose-escalation trial of the oral 
cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule 
in participants with advanced cancer. Clin Cancer Res. 2012;18(2):568-76. 
doi:10.1158/1078-0432.CCR-11-0509. 
89.  
Slamon DJ, Hurvitz S a., Applebaum S, et al. Phase I study of PD 0332991, cyclin-D 
kinase (CDK) 4/6 inhibitor in combination with letrozole for first-line treatment of 
participants with ER-positive, HER2-negative breast cancer. J Clin Oncol 2815s, 2010 
(suppl; abstr 3060). Available at: http://meetinglibrary.asco.org/content/50680-74. 
Accessed August 20, 2015. 
90.  
Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in 
postmenopausal participants with HR(+) breast cancer: BOLERO-2 final progression-free 
survival analysis. Adv Ther. 2013;30(10):870-84. doi:10.1007/s12325-013-0060-1.  
 
 


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76 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Participants and Their 
Caregivers and Non-Study Healthcare Team 
 
The participant ____________________________ is enrolled on a clinical trial using the 
experimental agents palbociclib (Ibrance®), everolimus (Afinitor®) and exemestane 
(Aromasin®).  This form is addressed to the participant, but includes important information for 
others who care for this participant.  
 
Both palbociclib and everolimus may interact with many drugs that are processed by your liver.  
Because of this, it is very important to tell your study doctors about all of your medicine before 
you start this study.  It is also very important to tell them if you stop taking any regular medicine, 
or if you start taking a new medicine while you take part in this study.  When you talk about your 
medicine with your study doctor, include medicine you buy without a prescription at the drug store 
(over-the-counter remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
Palbociclib and everolimus interact with a certain specific enzyme in your liver.  
• The enzyme in question is CYP3A, and both palbociclib and everolimus are broken down 
by this enzyme in order to be cleared from your system. 
• Palbociclib and everolimus must be used carefully with other medicines that need these liver 
enzymes to be effective or to be cleared from your system.   
• Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
o Moreover, both palbociclib and everolimus are considered inhibitors of the enzyme, 
meaning that it can affect the levels of other drugs that are processed by that 
enzyme.  This can lead to harmful side effects and/or reduce the effectiveness of 
those medications.    
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to switch 
any medicines that are considered “moderate or strong inducers/inhibitors or substrates of 
CYP3A.” 
• Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s usually 
big and catches your eye.  They also have a generic name—it’s usually small and located 
above or below the brand name, and printed in the ingredient list.  Find the generic name 
and determine, with the pharmacist’s help, whether there could be an adverse interaction.   
• Be careful:  


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78 
o If you take acetaminophen regularly:  You should not take more than 4 grams a day 
if you are an adult or 2.4 grams a day if you are older than 65 years of age.  Read 
labels carefully, acetaminophen is an ingredient in many medicines for pain, flu, 
and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort until 
the study is over. 
 
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. 
 
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement.  
 
• Your regular prescriber should check a medical reference or call your study 
doctor before prescribing any new medicine for you.  Your study doctor’s 
name is  
 
 
 
_____________________________________  
 
 
and he or she can be contacted at  
 
 
_____________________________________ 
 
 


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79 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agents 
palbociclib, everolimus and exemestane.  Palbociclib and everolimus 
interact with drugs that are processed by your liver.  Because of this, 
it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, and pharmacist) that you are taking part in a clinical 
trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
Palbociclib and everolimus interact with a specific liver enzyme 
called CYP3A, and must be used very carefully with other medicines 
that interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  


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80 
Table B-1 – Medications that can moderately or strongly inhibit or strongly induce CYP3A 
Medications that inhibit CYP3A 
Medications that induce CYP3A 
Amprenavir 
Aprepitant 
Atazanavir 
Boceprevir 
Clarithromycin 
Conivaptan 
Delavirdine 
Diltiazem 
Erythromycin 
Fluconazole 
Fosamprenavir 
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir 
Mibefradil 
Miconazole 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Verapamil 
Voriconazole 
Grapefruit, grapefruit juice, or any product containing 
grapefruit 
Carbamazepine 
Felbamate 
Nevirapine 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentin 
St. John’s wort 
The list provided below is not exhaustive.  For a more comprehensive, frequently updated list, please visit: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. 
 
 
 
 
 


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81 
APPENDIX C DRUG DIARY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Version Date: October 18, 2017 
 
82 
Study Participant Self-Administration 
Patient Drug Diary 
DF/HCC 
 
Patient Identifier: 
 
Protocol Number:  
16-177 
Your MD: 
 
Phone:  
Your RN: 
 
Phone:  
 
STUDY DRUG INSTRUCTIONS 
Study Drug A: 
Study Drug B: 
Study Drug C: 
Palbociclib 
Everolimus 
Exemestane 
 
Drug A 
(Palbociclib) 
How Much: 
Your dose is: ____________________________________________________. 
How Often: 
When: 
You will take each dose once per day for 21 consecutive days. 
You should take your dose within 1 hour of a meal at the same time each day. 
 
Drug A 
(Everolimus) 
How Much: 
Your dose is: ____________________________________________________. 
How Often: 
When: 
You will take each dose once per day. 
You should take your dose within 1 hour of a meal at the same time each day. 
 
Drug A 
(Exemestane) 
How Much: 
Your dose is: ____________________________________________________. 
How Often: 
When: 
You will take each dose once per day. 
You should take your dose within 1 hour of a meal at the same time each day. 
 
 
SPECIAL INSTRUCTIONS:  
 
• You should take all three drugs at the same time each day.   
 
 
 
• If it is more than 4 hours after your regularly scheduled time, do not take that day’s dos  
• If you inadvertently take 1 extra dose during a day, you must skip the next day’s dose. 
 
• If you vomit your dose, do not retake the dose. 
 
 
 
 
• The study drugs are to be swallowed whole, and not to be chewed, crushed, or opened.  
• Please avoid eating grapefruit.   
 
 
 
 
 
• Remember to bring any unused study drug, all empty containers, and this diary with you to 
your next visit. 
 
• During cycle 1, you should take your dose of all three drugs in the morning.  


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Protocol Version Date: October 18, 2017 
 
83 
  PLEASE INDICATE THE DATE, DOSE TAKEN, AND ANY COMMENTS: 
 
DOSING LOG 
 
CYCLE: ___________ 
 
 
For each dose days 1-21 take:  
1 capsule of Palbociclib 
1 tablet of Everolimus 
1 tablet of Exemestane 
 
 
 
For each dose days 21-28 take:  
1 tablet of Everolimus 
1 tablet of Exemestane 
 
Date 
Amount Taken 
Time Taken 
Taken within 1 
hour of a meal? 
 
Palbociclib 
Everolimus 
Exemestane 
hh:mm AM/PM 
Y/N 
Ex: 
1/6/2014 
1 
2 
1 
8:00 AM 
Y 
Day 1 
 
 
 
 
 
 
Day 2 
 
 
 
 
 
 
Day 3 
 
 
 
 
 
 
Day 4 
 
 
 
 
 
 
Day 5 
 
 
 
 
 
 
Day 6 
 
 
 
 
 
 
Day 7 
 
 
 
 
 
 
Day 8 
 
 
 
 
 
 
Day 9 
 
 
 
 
 
 
Day 10 
 
 
 
 
 
 
Day 11 
 
 
 
 
 
 
Day 12 
 
 
 
 
 
 
Day 13 
 
 
 
 
 
 
Day 14 
 
 
 
 
 
 
Day 15 
 
 
 
 
 
 
Day 16 
 
 
 
 
 
 
Day 17 
 
 
 
 
 
 
Day 18 
 
 
 
 
 
 
Day 19 
 
 
 
 
 
 
Day 20 
 
 
 
 
 
 
Day 21 
 
 
 
 
 
 
Day 22 
 
 
 
 
 
 
Day 23 
 
 
 
 
 
 
Day 24 
 
 
 
 
 
 
Day 25 
 
 
 
 
 
 
Day 26 
 
 
 
 
 
 
Day 27 
 
 
 
 
 
 
Day 28 
 
 
 
 
 
 


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84 
For Study Team Use Only 
 
Staff initials: 
Date dispensed: 
Date returned: 
# pills/caps/tabs dispensed:  
# pills/caps/tabs returned:  
# pills/caps/tabs that should have been taken: 
Discrepancy note:  
 


Protocol #16-177: Drafted (6/21/16) (LK)/ Approved: 8/9/2016 MML 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
16-177 
Protocol Name: 
A Phase 1b/2a Study Of Palbociclib In Combination With Everolimus And Exemestane In 
Postmenopausal Women With Estrogen Receptor Positive and HER2 Negative Metastatic 
Breast Cancer. 
DFCI Site PI: 
Sara Tolaney, MD MPH 
DFCI Research Nurse: 
Margaret Haldoupis, Elizabeth Kasparian, Kathleen Roche, Victoria Brock 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
 
 
Palbociclib (PD-0332991), an orally active pyridopyrimidine, is a potent first-in-class, highly selective reversible 
inhibitor of CDK4 and CDK6. (Section 2.4.1) 
 
Everolimus is a selective mTOR inhibitor, specifically targeting the mTOR-raptor signal transduction complex 1. 
(Section 2.4.2) 
 
Exemestane is an irreversible steroidal Aromatase inhibitor. (Section 2.4.3) 
 
The Study Design is in Section 1.1. 
 
The Study Rationale is in Section 2.5. 
 
A cycle is defined as 28 days. (Section 1.1) 
Dose 
Calc. 
 
Palbociclib is dosed in fixed dosing. (Section 5.1 and 5.5) 
 
Everolimus is dosed in fixed dosing. (Section 5.1 and 5.5) 
 
Exemestane is dosed in fixed dosing. (Section 5.1 and 5.5) 
 
Study Drug  
Administration 
Agent Administration Guidelines are found in Section 5.0. 
 
Palbociclib, Everolimus, and Exemestane are taken orally once per day. (Section 5.1) 
 
Palbociclib is taken orally, once per day within 1 hour of a meal for 21 consecutive days followed by a 7-day 
rest period (28-day cycle). (Section 5.7.1) Administration instructions are in Section 5.7.1. 
 
Everolimus is taken orally, once per day within 1 hour of a meal. Treatment is continuous daily to complete a 28 
day cycle. (Section 5.7.2)  Administration instructions are in Section 5.7.2. 
 
Exemestane is taken orally, once per day within 1 hour of a meal. Treatment is continuous daily to complete a 
28 day cycle. (Section 5.7.3)  Administration instructions are in Section 5.7.3. 
 
All 3 drugs should be taken at the same time each day. (Appendix C – Drug Diary)  
 
For Palbociclib, Everolimus, and Exemestane: If a dose is vomited, a replacement dose should NOT be taken.  
If a dose is missed (defined as 4hours from regularly scheduled dose time), it should be skipped and NOT 
made-up. Participants who inadvertently take 1 extra dose during a day must skip the next day’s dose. 
(Sections 5.7.1, 5.7.2, and 5.7.3) 
 
For Palbociclib, Everolimus, and Exemestane: Capsules should be swallowed whole and not chewed, crushed 
or opened.  (Sections 5.7.1, 5.7.2, and 5.7.3) 
 
Criteria to treat are in Section 5.6. 
 
With Palbociclib and Everolimus participants must avoid consumption of grapefruit. (Sections 5.7.1 and 5.7.2) 
Dose  
Mods & 
Toxicity 
Dose Modifications/Dosing Delays for Toxicity are outlined in Section 6.0. 
 
This protocol uses NCI CTCAE criteria, version 4.0. (Section 5.2) 
 
The definition of a DLT is found in Section 5.2. 
Con 
Meds 
Concomitant Therapy Guidelines are in Section 5.8 and in Appendix B. 
 
Please review the cited sections for permitted, prohibited, and “use with caution” medications/therapies/foods 
Required  
Data  
Study Calendar and Assessment Required data are outlined in Sections 9.0 and 10.0. 
 
The study calendar is in Section 10.0. 
 
Vital signs: The time points are in Table 10-1, Section 10.0. 
 
ECGs:  Single 12-lead EKG. The time points are in Table 10-1, Section 10.0. 
 
PKs: The time points are in Sections 9.1 and 9.2 as well as Table 10-1, Section 10.0. 
 
Biomarkers: The time points are in Section 9.3 as well as Table 10-1, Section 10.0. 


Protocol #16-177: Drafted (6/21/16) (LK)/ Approved: 8/9/2016 MML 
 
Charting 
Tips 
All study drugs require documentation of exact administration time. 
Please be sure to also DOCUMENT any required observation periods, any additional vital signs, routes of 
administration, and exact time of PK collections.