Palbociclib After CDK and Endocrine Therapy (PACE): A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-treated ER+/HER2- Metastatic Breast Cancer
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Sponsor: Dana-Farber Cancer Institute

1 
 
 
DF/HCC Protocol #: 17-101 
 
TITLE:  Palbociclib After CDK and Endocrine Therapy (PACE): A Randomized Phase II 
Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-treated ER+/HER2- 
Metastatic Breast Cancer 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
Principal Investigator (PI): 
Erica L. Mayer, MD, MPH 
 
Breast Oncology Center 
 
Dana-Farber Cancer Institute 
 
450 Brookline Ave. 
 
Boston, MA 02215 
 
Ph: 617-632-2335 
 
Fax: 617-632-1930 
 
E-mail address: emayer@partners.org 
 
 
 
Statistician:  
Meredith Regan ScD 
 
Dana-Farber Cancer Institute 
 
 
Project Manager:  
Michelle DeMeo 
 
Dana Farber Cancer Institute 
ctopm@dfci.harvard.edu  
 
 
  
 
 
Industry (Pfizer)-Supplied Agents:  Palbociclib, Avelumab 
Other Agent(s):  Fulvestrant, supplier: commercial  
 
IND #:  133848 
IND Sponsor:  Erica Mayer, MD, MPH   
 
Protocol Type / Version # / Version Date: Protocol / Version 4 / March 3, 2020 

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SCHEMA 
 
N=220 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility: 
• HR+/HER2 -
Metastatic Breast 
cancer    
• Progression on AI 
+ CDK4/6 inhibitor 
• 0-1 prior chemo 
lines 
 
 
R
A
N
D
O
M
I
Z
A
T
I
O
N 
Tumor 
measurements 
q8 weeks x 24 
weeks, then q 
12 weeks  
CR, PR, SD 
Continue 
treatment 
Arm B and C-PD, 
or any Arm: 
Toxicity requiring 
discontinuation 
Off treatment, 
Safety follow-
up30 days after 
last dose of 
treatment 
A: Fulvestrant 
B: Fulvestrant with 
upfront Palbociclib  
C: Fulvestrant, 
Palbociclib, 
Avelumab 
Arm A-PD: 
Palbociclib 
Continue 
treatment 
1:2:1 
Stratification: 
Exposure to a chemotherapy regimen between initial exposure  
to CDK4/6 inhibitor and entry on this study (Yes/No) 
 

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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES and Endpoints ..............................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objective ....................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
1.4 
Exploratory Objectives ............................................................................................6 
1.5 
Correlative Objectives .............................................................................................7 
1.6 
Endpoints .................................................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Hormone Receptor Positive Breast Cancer..............................................................7 
2.2 
Palbociclib Mechanism of Action ............................................................................8 
2.3 
Palbociclib Preclinical Data and Pharmacokinetic Studies .....................................9 
2.4 
Palbociclib Clinical Data .......................................................................................13 
2.5 
Mechanisms of Resistance to Palbociclib and Endocrine Therapy .......................14 
2.6 
Immunotherapy in HR+/HER2- Breast Cancer .....................................................15 
2.7 
Avelumab Mechanism of Action ...........................................................................15 
2.8 
Avelumab Pharmacokinetic Data and Dose Selection...........................................17 
2.9 
Avelumab Clinical Data .........................................................................................18 
2.10 
Rationale ................................................................................................................21 
3. 
PARTICIPANT SELECTION ...........................................................................................22 
3.1 
Eligibility Criteria ..................................................................................................22 
3.2 
Exclusion Criteria ..................................................................................................24 
3.3 
Inclusion of Women and Minorities ......................................................................26 
4. 
REGISTRATION PROCEDURES ...................................................................................26 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................26 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................27 
4.3 
General Guidelines for Other Investigative Sites ..................................................27 
4.4 
Registration Process for Other Investigative Sites.................................................27 
5. 
TREATMENT PLAN ........................................................................................................28 
5.1 
Treatment Regimen ................................................................................................28 
5.2 
Pre-Treatment Criteria ...........................................................................................29 
5.3 
Agent Administration.............................................................................................30 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................31 
5.5 
Crossover Therapy .................................................................................................33 
5.6 
Criteria for Removal from Treatment ....................................................................34 
5.7 
Follow Up ..............................................................................................................34 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................35 
6.1 
Palbociclib..............................................................................................................35 
6.2 
Fulvestrant..............................................................................................................39 

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6.3 
Avelumab ...............................................................................................................39 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................47 
7.1 
Expected Toxicities ................................................................................................48 
7.2 
Adverse Event Characteristics ...............................................................................50 
7.3 
Serious Adverse Event Reporting ..........................................................................50 
7.4 
DF/HCC Adverse Event Expedited Reporting Guidelines ....................................51 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ......................51 
7.6 
Expedited Reporting to Pfizer ................................................................................51 
7.7 
Expedited Reporting to Hospital Risk Management .............................................53 
7.8 
Routine Adverse Event Reporting .........................................................................53 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................53 
8.1 
Palbociclib..............................................................................................................53 
8.2 
Fulvestrant..............................................................................................................57 
8.3 
Avelumab ...............................................................................................................58 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................60 
9.1 
Correlative Studies Background ............................................................................60 
9.2 
Specimen Submission Requirements .....................................................................61 
9.3 
Translational Research Blood ................................................................................62 
9.4 
Tumor Biopsies ......................................................................................................63 
9.5 
Archival Tissue Collection ....................................................................................63 
10. 
STUDY CALENDAR .......................................................................................................64 
11. 
MEASUREMENT OF EFFECT........................................................................................67 
11.1 
RC: RECIST Criteria .............................................................................................67 
11.2 
irRC: Immune-Related Response Criteria .............................................................75 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................79 
12.1 
Data Reporting .......................................................................................................79 
12.2 
Data Safety Monitoring..........................................................................................79 
12.3 
Multicenter Guidelines...........................................................................................79 
12.4 
Collaborative Research and Future Use of Data and Biospecimens ......................80 
13. 
STATISTICAL CONSIDERATIONS...............................................................................80 
13.1 
Accrual and Sample Size Determination ...............................................................80 
13.2 
Analysis Populations ..............................................................................................81 
13.3 
Analysis of Efficacy Endpoints .............................................................................81 
13.4 
Comparison of RECIST versus irRC (arm C) .......................................................83 
13.5 
Safety .....................................................................................................................83 
13.6 
Interim Efficacy/Inefficacy Monitoring .................................................................83 
13.7 
Correlative Objectives ...........................................................................................84 
14. 
PUBLICATION PLAN .....................................................................................................85 
15. 
REFERENCES ..................................................................................................................86 

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APPENDIX A: Eastern Cooperative Oncology Group (ECOG) Performance Status Criteria .....91 
APPENDIX B: Strong CYP3A Inducers/Inhibitors and Information on Possible Drug 
Interactions .........................................................................................................................92 
APPENDIX C: Palbociclib drug diary ..........................................................................................93 
APPENDIX D: Common Terminology Criteria for Adverse Events (version 4.0) ......................94 
APPENDIX E: RESEARCH SPECIMEN COLLECTION GUIDELINES ..................................95 
APPENDIX F: Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring 
Plan ....................................................................................................................................97 
 
 
 
 

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1. OBJECTIVES AND ENDPOINTS 
 
1.1 
Study Design 
 
This is a randomized phase II pilot study designed to evaluate the utility of palbociclib therapy 
(with fulvestrant) or PD-L1 checkpoint blockade (with fulvestrant) in patients with advanced 
ER+/HER2- breast cancer that has progressed despite prior CDK4/6 inhibition with endocrine 
therapy. At least 220 eligible patients will be randomized 1:2:1 to receive fulvestrant alone (Arm 
A: approximately 55 patients), fulvestrant plus palbociclib (Arm B: approximately 110 patients), 
or fulvestrant plus avelumab plus palbociclib (Arm C: approximately 55 patients). Patients will be 
stratified by whether there was exposure to a chemotherapy regimen between initial exposure to 
CDK4/6 inhibitor and entry on this study, to determine if a break from CDK4/6 inhibition increases 
CDK4/6 inhibitor sensitivity. 
 
1.2 
Primary Objective 
 
To evaluate progression-free survival (PFS) using traditional RECIST criteria with the 
combination of fulvestrant and palbociclib vs. fulvestrant alone in patients with advanced 
HR+/HER2- breast cancer that has progressed despite prior CDK4/6 inhibition and endocrine 
therapy.  
 
1.3 
Secondary Objectives 
 
• To assess the objective response rate (ORR) of fulvestrant + palbociclib vs fulvestrant alone 
in patients with advanced ER+/HER2- breast cancer that has progressed despite prior CDK4/6 
inhibition and endocrine therapy 
• To assess the PFS and ORR with addition of palbociclib after progression on fulvestrant alone 
in patients with advanced ER+/HER2- breast cancer that has progressed despite prior CDK4/6 
inhibition and endocrine therapy using traditional RECIST criteria 
• To assess the PFS and ORR for fulvestrant, palbociclib + avelumab vs fulvestrant alone in 
patients with advanced ER+/HER2- breast cancer that has progressed despite prior CDK4/6 
inhibition and endocrine therapy using traditional RECIST criteria 
• To assess the PFS and ORR for fulvestrant, palbociclib + avelumab vs fulvestrant + palbociclib 
in patients with advanced ER+/HER2- breast cancer that has progressed despite prior CDK4/6 
inhibition and endocrine therapy using traditional RECIST criteria 
• Safety and tolerability of all agents 
 
1.4 
Exploratory Objectives 
 
• To compare PFS and ORR in the stratified subset of patients where there was exposure to a 
chemotherapy regimen between initial exposure to CDK4/6 inhibitor and entry on this study. 
• To compare response to therapy with fulvestrant, palbociclib + avelumab using traditional 
RECIST criteria versus arc criteria 
• Assessment of outcomes in predefined molecular subgroups including: 
o ESR mutation 
o PI3K mutation 

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o Loss of Rb gene and/or function 
 
1.5 
Correlative Objectives 
 
• To determine the frequency and distribution of Rb loss or loss of function mutation, ESR 
mutations, and PI3 kinase mutations in tumors with demonstrated resistance to prior CDK4/6 
inhibitor and endocrine therapy, as well as response to therapy by arm. 
• To evaluate cyclin E levels in patients who had exposure to a chemotherapy regimen between 
initial exposure to CDK4/6 inhibitor and entry on this study, versus those who did not receive 
intervening chemotherapy 
• Explore tissue and cfDNA-based markers predictive of resistance or response to protocol 
therapy after prior progression on CDK4/6 and endocrine therapy in ER+ breast cancer, not 
excluding copy numbers of CCND1 and CDKN2A, proteins (eg, Ki67, pRb, CCNE1), and 
RNA expression (e.g., RB, Cyclin D, E cdk4, cdk6) 
• Explore tissue and cfDNA-based markers predictive of response to palbociclib in ER+ breast 
cancer 
• Explore tissue and cfDNA-based markers predictive of response to PD-L1 inhibition in ER+ 
breast cancer, including immune signature.  
 
1.6 
Endpoints 
 
1.6.1 Primary Endpoint 
 
• Progression-Free Survival (PFS) 
 
1.6.2 Secondary Endpoints 
 
• Objective Response (ORR: Complete Response or Partial Response) 
• Duration of Response (DOR) 
• Clinical Benefit Response (CBR) 
• Type, incidence, severity (as graded by NCI CTCAE Version 4.0), seriousness and 
relationship to study medications of adverse events (AE) and any laboratory 
abnormalities 
 
2. BACKGROUND 
 
2.1 
Hormone Receptor Positive Breast Cancer 
 
Hormone receptor positive (HR+) breast cancer is the most commonly diagnosed subset of breast 
cancer, and affects thousands of patients every year. Endocrine therapy is highly effective for this 
subset of breast cancer, and standard adjuvant management for women with HR+ breast cancer 
includes adjuvant endocrine therapy for at least 5 years. Despite this effective therapy, a percentage 
of patients will relapse with incurable metastatic disease, likely related to the development of 
resistance to endocrine therapy.  
 

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A variety of novel agents are in development to improve the efficacy of endocrine therapy 
against HR+ breast cancer. These include compounds that halt progression through the cell cycle 
via inhibition of the CDK4/6 kinases. Palbociclib, a CDK4/6 inhibitor, has been approved for the 
treatment of metastatic HR+/HER2- negative breast cancer both in the first-line setting with 
concurrent aromatase inhibition (PALOMA-1, the findings were confirmed in PALOMA-2), as 
well as in patients previously treated with endocrine therapy in combination with fulvestrant 
(PALOMA-3). Palbociclib plus letrozole has been added to the NCCN guidelines as a treatment 
option for first-line therapy for postmenopausal patients with ER-positive, HER2-negative breast 
cancer (NCCN Guidelines).  The most recently published ASCO on endocrine therapy for 
hormone receptor positive metastatic breast cancer also stated that a non-steroid aromatase 
inhibitor (AI) with palbociclib may be offered to treatment naïve HR+, HER2- metastatic breast 
cancer50.). Since palbociclib was launched in US in February 2015, more than 35,000 women 
have been treated with palbociclib in routine clinical care. In addition, other CDK4, 6 inhibitors, 
including ribociclib and abemaciclib, are approved for metastatic HR+ HER2- breast cancer as 
well.  .  
However, patients progress on CDK4/6 inhibitor containing regimens. Mechanisms governing 
resistance to CDK4/6 inhibitor therapy have not been fully elucidated, and it is unclear whether 
ongoing palbociclib therapy might be of benefit even after the development of clinical progression.   
 
2.2 
Palbociclib Mechanism of Action 
 
Cell cycle inhibition is a target of choice for novel cancer therapeutics. palbociclib, an orally active 
pyridopyrimidine, is a potent first-in-class, highly selective reversible inhibitor of CDK 4 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.3-5 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.5  CDK 
activity and G1 progression is negatively regulated by Cip-Kip and INK4 family, typified by p16.6-
10 Overexpression of p16 in cells with normal Rb inhibits both CDK4-and CDK6-associated kinase 
activity and Rb phosphorylation, with subsequent cell cycle arrest.11,12 
 
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.13 Cyclin D1 is a direct transcriptional 
target of ER14-17 and microinjection of antibodies to cyclin D1 inhibits estrogen-induced S-phase 
entry.18-22 In addition, anti-estrogen-induced growth arrest of ER+ breast cancer cells is 
accompanied by decreased cyclin D1 expression23 while endocrine resistance is associated with 
persistent cyclin D1 expression and Rb phosphorylation.24 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 activity25 and CDK4/6 inhibitors are most effective in tumors with gene 
amplification and overexpression of cyclin D1,26-28 which is common in ER+ breast cancer.  For 
example, palbociclib was most effective for ER+ breast cancer in a cell line panel,29 including 
those that exhibited anti-estrogen resistance. Genetic aberrations leading to hyperactivation of 

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cyclin D1-CDK4/6 is particularly common in ER+ breast cancer, consistent with its critical role in 
the tumorigenesis of this cancer subtype,29 making CDK4/6 inhibitors particularly attractive agents 
for ER+ breast cancer.   
 
Preclinical data, both Pfizer internal data and also from other laboratories, suggest that estrogen 
resistant models are exquisitely sensitive to the combination of palbociclib with antihormonal 
therapy or palbociclib alone.  Blockade of the ER signaling pathway is synergistic with cell cycle 
arrest induction, as demonstrated by the more than doubling in median PFS observed in Study 
A5481003 (Study 1003; PALOMA-1) in combination with letrozole in post-menopausal women 
with ER-positive advanced breast cancer34  which resulted in the accelerated approval in the US 
in February 2015.  
 
2.3 
Palbociclib Preclinical Data and Pharmacokinetic Studies 
 
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 vivo27 
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.27  
 
Treatment of cultured tumor cells with palbociclib causes growth arrest that is accompanied by 
the inhibition of specific pRb phosphorylation by CDK4 or CDK6 on residues serine -780 
and -795 of pRb.  The IC50 values for reduction of pRb phosphorylation at serine -780 and -795 
in MDA-MB-435 breast carcinoma cells were 0.066 and 0.063 µM, respectively.  The IC50 
values for reduction of pRb phosphorylation are similar to the IC50 values of inhibition of 
thymidine incorporation across a range of cultured tumor and normal cells. 
 
Palbociclib was tested in vitro on molecularly characterized human breast cancer cell lines.  
Results from these experiments indicate that those cell lines that are more sensitive to palbociclib 
(IC50 < 150 nM) have low levels of CDKN2A (p16) and high levels of Rb, while resistant cell 
lines show the opposite characteristics.  Of note for this study, ER+ breast cancer seems to be 
particularly appropriate for treatment with palbociclib; sensitive cell lines in this panel represent 
mostly the luminal ER+ subtype.29  
 
The combination of palbociclib with tamoxifen has been tested in vitro in ER+ human breast 
cancer cell lines indicating a synergistic interaction29 and provided a biologic rationale for 
evaluating the combination of palbociclib with anti-hormonal therapy in the clinic. Also, most 
recent data from Julie Kan’s group in hormone resistant models (MCF7-CYP19) indicate a 
significant benefit from the combination of palbociclib and letrozole as well as palbociclib and 
fulvestrant over single agent letrozole and fulvestrant (Pfizer, unpublished data). 
 
Once daily oral administration of palbociclib was well tolerated in rats at levels of 10 mg/kg/day 
for males and up to 200 mg/kg/day for females43.  
 
Palbociclib has been evaluated in safety pharmacology, genetic toxicity, reproductive and 

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development (fertility and early embryonic development, embryofetal development), and repeat-
dose toxicity studies of up to 15-weeks duration in the rat and dog.  Based on the nonclinical 
safety studies conducted with palbociclib, the primary palbociclib-related systemic toxicities 
were observed in hematolymphopoietic tissues (decreased cellularity, increased iron pigment, 
decreases in peripheral leukocytes and RBC parameters) and male reproductive organs 
(degeneration of seminiferous tubules, secondary epididymal hypospermia and increased 
intratubular cellular debris).  Partial to complete reversibility of toxicities was demonstrated 
following a 4 week recovery period, with the exception of the male reproductive organ findings 
in the dog.  These toxicities occurred in both rats and dogs, and are consistent with the intended 
pharmacologic effect of palbociclib (i.e., cell cycle inhibition). (Fink et al, 2001; Arguello et al, 
1998; Bartkova et al, 2003). Palbociclib was also identified with the potential to cause QT 
prolongation, developmental effects, and aneugenicity.  Developmental effects that were 
considered adverse included a decrease in fetal body weights in rats and a low incidence of small 
phalanges on the forepaws in rabbits. A no effect level for aneugenicity was observed at 
approximately 7-fold higher than unbound systemic AUC24 exposures associated with the 
human clinical dose of 125 mg QD. 
  
Palbociclib is being further evaluated for chronic toxicity in a 6-month rat and 9-month dog 
repeat-dose toxicity study. Cataracts have been identified in rats following 27-weeks of 
intermittent dosing. The minimal dose level for cataract formation has not been identified from 
the 27-week rat toxicity study, based on the histological data (lens degeneration was noted 
microscopically). Cataracts were identified from ophthalmic evaluations at the lower examined 
dose of 30 mg/kg/day in males but at no dose in females. 
 
Further data from this toxicity study suggested a correlation between altered glucose metabolism 
and the formation of cataracts/lens degeneration. In dog toxicity studies (15-week and 39-week), 
no altered glucose levels or cataracts/lens degeneration have been observed (lack of lens 
degeneration not yet confirmed in the 39-week study; histopathology pending). Hyperglycemia 
and diabetes mellitus are not considered to be identified clinical risks and are not considered to 
be adverse drug reactions (ADRs) of palbociclib.  
 
Human Pharmacokinetic (PK) Data 
In the first-in-human Study A5481001, the exposure (area under the concentration-time curve 
from time 0 to 10 hours [AUC(0-10)] and maximum concentration [Cmax]) increased in a dose 
proportional manner over the dose range of 25 to 225 mg QD on Schedules 3/1 and 2/1 
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.  In 
Study 1003, following repeated daily dosing to steady state, palbociclib was absorbed with a 
median time to reach maximum concentration (Tmax) of ~7.9 hours.  The mean palbociclib 
apparent volume of distribution (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 (t½) was 28.8 hours and the 
geometric mean CL/F (apparent clearance of drug from plasma) was 63.1 L/hour.  Steady state 
was reached within 8 days after the start of palbociclib dosing.  Palbociclib accumulated 
following repeated dosing with a median accumulation ratio (Rac) of 2.4, which is consistent with 
the terminal half-life. 

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Food Effect 
Study A5481021 was a randomized, open-label, single-dose, 4-sequence, 4-period crossover 
study to evaluate the effect of food on oral bioavailability of the palbociclib commercial free 
base capsule formulation in healthy subjects.  The study results indicate that palbociclib 
absorption and exposure were very low in approximately 13% of the population under the fasted 
condition.  Food intake increased the palbociclib exposure in this small subset of the population, 
but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent.  
Administration of palbociclib with or in between meals significantly reduced the intersubject 
variability (%CV) of AUCinf (area under the concentration-time curve from time zero to infinity) 
and Cmax, from 39% for AUCinf and 73% for Cmax under overnight fasted conditions to 23% to 
27% for AUCinf and 21% to 24% for Cmax under fed conditions, irrespective of the fat and calorie 
content of the food.  Based on these findings, palbociclib should be taken with food. 
Antacid Effect 
The solubility of the palbociclib free base is pH dependent; palbociclib is water soluble at low 
pH (2.1 – 4.5), while the solubility dramatically decreases as pH rises above 4.5.  Concomitant 
administration of agents which increase gastric pH can alter the solubility and absorption of 
palbociclib free base formulations.   
In a drug-drug interaction study in healthy subjects (Study A5481038), coadministration of a 
single dose of 125 mg palbociclib free base capsule with multiple doses of a proton pump 
inhibitor (PPI), rabeprazole, under fed conditions decreased palbociclib Cmax by 41% but had 
limited impact on AUCinf (13% decrease) compared with a single dose of palbociclib 
administered alone.  This 13% reduction in overall exposure is considered not clinically relevant.  
The results also indicated that administration of palbociclib under fed conditions with staggered 
dosing of an H2-receptor antagonist (H2RA), famotidine, and staggered dosing of a local 
antacid, Mi-Acid Maximum Strength Liquid, had no impact on the exposure of palbociclib.  
Given the reduced effect on gastric pH of H2RAs and local antacids compared to PPIs, the effect 
of these acid-reducing agents when given simultaneously with palbociclib free base capsules 
under fed conditions is expected to be minimal.34,35 In another healthy subject study (Study 
A5481018), coadministration of a single dose 125 mg palbociclib free base capsule with multiple 
doses of rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 
80%, respectively, when compared with a single dose of palbociclib administered alone. 
Collectively, these antacid drug-drug interaction (DDI) data further support the requirement that 
the free base capsule of palbociclib should be taken with food. 
Beginning in March-May 2020, Pfizer will be switching from a capsule to tablet formulation for 
palbociclib in the United States. The new tablet formulation of palbociclib may be taken with or 
without food, unlike the capsule formulation. Additionally, unlike the capsule formulation, the 
tablet formulation can be taken with proton pump inhibitors (PPI)/antacids and does not contain 
lactose (dairy) or gelatin, which may be important for patients with tolerability issues and/or 
dietary preferences. 
 
 

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Metabolic Drug Interaction 
In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the 
metabolism of palbociclib.  In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 
2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant 
concentrations. 
The effect of multiple dosing of palbociclib 125 mg QD on the single-dose PK of a sensitive 
CYP3A4/5 probe substrate, midazolam (2 mg), was evaluated in 26 healthy women of non-
childbearing potential in Study A5481012.  Coadministration of midazolam and palbociclib 
increased midazolam AUCinf and Cmax by 61% and 37%, respectively, relative to midazolam 
given alone.  These results indicate that palbociclib is a weak time-dependent inhibitor of 
CYP3A. 
An itraconazole DDI study in healthy subjects (Study A5481016) and a rifampin DDI study in 
healthy subjects (Study A5481017) were conducted to evaluate the potential for strong CYP3A 
inhibitors and inducers, respectively, to alter the PK of palbociclib.  Coadministration of 
itraconazole and palbociclib increased palbociclib AUCinf and Cmax by approximately 87% and 
34%, respectively, relative to when palbociclib was given alone.  Coadministration of rifampin 
and palbociclib decreased palbociclib AUCinf and Cmax by approximately 85% and 70%, 
respectively, relative to when palbociclib was given alone.  Based on these results, the 
concurrent administration of strong CYP3A inhibitors and inducers with palbociclib should be 
avoided. 
Coadministration of Palbociclib and Fulvestrant 
Study A5481023 was a randomized, double-blind, Phase 3 study conducted to assess the 
efficacy, safety, and PK of palbociclib administered in combination with fulvestrant with or 
without goserelin versus placebo plus fulvestrant with or without goserelin for the treatment of 
HR-positive/HER-2 negative advanced breast cancer that progressed on prior endocrine therapy.  
The study included limited PK sampling (steady-state trough samples) to confirm the lack of a 
clinically significant DDI between palbociclib and fulvestrant or between palbociclib and 
goserelin.  The concurrent administration of fulvestrant did not have a clinically relevant impact 
on the plasma PK of palbociclib.  Likewise, the concurrent administration of palbociclib did not 
have a clinically relevant impact on the plasma PK of fulvestrant.  Therefore, there is no 
clinically relevant DDI between palbociclib and fulvestrant when they are coadministered. 
Coadministration of Palbociclib and Goserelin 
The concurrent administration of goserelin did not have a clinically relevant impact on the 
plasma PK of palbociclib in Study A5481023.  Likewise, the concurrent administration of 
palbociclib did not have a clinically relevant impact on the plasma PK of goserelin.  Therefore, 
there is no clinically relevant DDI between palbociclib and goserelin when they are 
coadministered. 
 

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2.4 
Palbociclib Clinical Data 
 
Palbociclib has been tested in a Phase 1 dose escalation trial (Study A5481001) in 74 patients 
with advanced cancer.  Two dosing schedules were evaluated:  Schedule 3/1 (3 weeks on 
treatment followed by 1 week off treatment; n=41) at doses ranging from 25 to 150 mg and 
Schedule 2/1 (2 weeks on treatment followed by 1 week off treatment; n=33) at doses ranging 
from 100 to 225 mg.  All dose limiting toxicities (DLTs) observed in this study were related to 
myelosuppression and mainly consisted of Grade 3 neutropenia lasting more than 7 days after the 
end of the treatment cycle.  However, neutropenia was reversible and non-cumulative.  The most 
common non-hematological adverse events included fatigue, anemia, diarrhea, constipation, 
vomiting, and dyspnea, mostly mild to moderate severity.  A greater proportion of patients on 
Schedule 2/1 had treatment-related adverse events during and after Cycle 1 than patients on 
Schedule 3/1 although the proportion of patients with treatment-related neutropenia was similar 
with respect to the 2 dosing schedules, both during and after Cycle 1.  A total of 13/37 patients 
on Schedule 3/1 evaluable for efficacy experienced stable disease (SD), including 6 patients with 
SD lasting 40 weeks or longer.  Based on the relatively improved safety profile of Schedule 3/1 
and the efficacy results, Schedule 3/1 was selected for further clinical development and the 
Recommended Phase 2 Dose (RP2D) for this schedule was determined to be 125 mg/day.   
Palbociclib has been investigated in the following pivotal studies for the treatment of advanced 
breast cancer:  A5481003 (Study 1003), A5481008 (Study 1008), and A5481023 (Study 1023).   
Study 1003 was a Phase 1/2, randomized, open-label study designed to assess the efficacy and 
safety of palbociclib (125 mg QD on Schedule 3/1) in combination with letrozole 2.5 mg QD 
versus letrozole 2.5 mg QD alone for the first-line treatment of post-menopausal women with 
ER-positive/HER2-negative advanced breast cancer.  The results from the study demonstrated a 
statistically significant improvement in PFS for the palbociclib plus letrozole arm compared to 
the letrozole alone arm (20.2 vs. 10.2 months; HR=0.488 [95% CI: 0.319, 0.748]; p 
<0.001).Error! Reference source not found.  The most common adverse events reported for the 
palbociclib plus letrozole arm were hematologic events, mostly neutropenia and leukopenia that 
were reversible.  Based on the results from this study, palbociclib was granted accelerated 
approval in the US in combination with letrozole for the treatment of post-menopausal women 
with ER-positive/HER-2 negative advanced breast cancer as initial endocrine-based therapy for 
their metastatic disease.   
Study 1008 was a Phase 3, randomized, double-blind, placebo-controlled study designed to 
assess the efficacy and safety of palbociclib (125 mg QD on Schedule 3/1) plus letrozole 2.5 mg 
QD versus placebo plus letrozole 2.5 mg QD for the first-line treatment of post-menopausal 
women with ER-positive/HER2-negative advanced breast cancer.  The results from the study 
demonstrated a statistically significant improvement in PFS for the palbociclib plus letrozole arm 
compared to the placebo plus letrozole arm (24.8 vs. 14.5 months; HR=0.58 [95% CI: 0.46, 
0.72]; p <0.000001)37, confirming the significant clinical benefit and safety of palbociclib plus 
letrozole in ER-positive/HER2-negative advanced breast cancer who had not received prior 
systemic therapy for their advanced disease observed in Study 1003. 
Study 01010 was a Phase 3, randomized, double-blind, placebo-controlled study designed to 
assess the efficacy and safety of palbociclib (125 mg QD on Schedule 3/1) plus fulvestrant 500 

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mg versus placebo plus fulvestrant 500 mg for the treatment of women with HR-positive/HER2-
negative advanced breast cancer whose disease had progressed after prior endocrine therapy.  
The results from the study indicated that the addition of palbociclib to fulvestrant significantly 
prolongs PFS with the median PFS of 9.5 months (95% CI: 9.2, 11.0) for the palbociclib plus 
fulvestrant arm and 4.6 months (95% CI: 3.5, 5.6) for the placebo plus fulvestrant arm 
(HR=0.461 [95% CI: 0.360, 0.591]; p <0.0001)38. The adverse events observed in the study were 
consistent with the known safety profile of palbociclib.  Overall, palbociclib was well tolerated 
with adverse events managed by dosing interruptions, dose reductions, and/or standard medical 
care.  Based on the results from this study, palbociclib was approved in the US in combination 
with fulvestrant for the treatment of women with HR-positive/HER2-negative advanced breast 
cancer with disease progression following endocrine therapy. 
 
2.5 
Mechanisms of Resistance to Palbociclib and Endocrine Therapy 
 
Despite the promising evidence of clinical efficacy outlined above, a subset of patients manifest 
de novo resistance to the anti-estrogen/palbociclib combination and those that do not invariably 
develop resistance at some point in the future. Insights into the mechanisms governing resistance 
to both anti-estrogen therapy as well as CDK 4/6 inhibition remain limited and constitute and 
active area of clinical and basic scientific research. 
 
Early pre-clinical work with palbociclib revealed a set of 450 genes that were differentially 
expressed between resistant and sensitive cell lines29.These results seemed to indicate that genes 
associated with luminal breast cancers were enriched in the sensitive group. Loss of the tumor 
suppressor Rb was associated with resistance, and this has been borne out in subsequent studies. 
In a recent in vitro study, ER+ cell lines were grown in long-term culture with palbociclib to induce 
acquired resistance (Lenihan C SABCS 2015). These resistant clones were then profiled via 
western blot assay, RNA sequencing, and mass spectrometry in an effort to identify mediators of 
resistance. Sustained downregulation of Rb was identified, which was reversible upon drug 
withdrawal. Hyperactivation of the PI3K/mTOR and Rho/Rac pathways was also identified. 
Targeted drug screening revealed increased sensitivity of palbociclib-resistant cell lines to various 
inhibitors of AKT, PI3K, and MEK. A second recent study confirmed this work in vitro, suggesting 
that in palbociclib-resistant T47D ER+ cells, loss of Rb acts as a primary driver of resistance (Lee 
NV SABCS 2015). This work also revealed upregulation of various transcriptional effectors 
including E2F, TGFB, WNT, MYC, and NF-kB in MCF7 palbociclib-resistant cell lines that had 
retained Rb expression. Interestingly, in these MCF7 palbociclib-resistant cell lines, both cyclin 
E1 and cyclin A2 were found to be upregulated downstream of E2F. Given the redundant role of 
cyclin E/CDK2 in the regulation of Rb, knockdown of cyclin E was attempted via shRNA. This 
intervention was able to restore palbociclib sensitivity, suggesting that cyclin E may be a key 
mediator of resistance in this context. 
 
Mechanisms governing resistance to anti-estrogen blockade are also diverse and poorly 
understood. Many of the canonical signal transduction pathways alluded to above, including the 
PI3K/mTOR/AKT pathway, have been implicated in the development of estrogen-independence. 
Acquired mutations in the estrogen gene (ESR1) have also been described46.These mutations rarely 
occur in primary breast cancer, but appear to be enriched via selective pressure during course of 
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also appear to maintain at least some sensitivity to the selective estrogen degrader fulvestrant. 
ESR1 mutations have been identified via blood-based circulating free tumor DNA assays51 and 
this may serve as a rapid, non-invasive measure of de novo or emerging resistance in ER+ breast 
cancer. In a recent retrospective-prospective analysis, plasma ESR1 levels were assessed in a 
subset of patients treated on the PALOMA-3 study outlined above44. The presence of ESR1 
mutations (identified in more than 25% of patients) was associated with acquired resistance to 
prior aromatase inhibitor therapy. Both groups (with and without established ESR1 mutations) 
benefited from combination therapy with fulvestrant and palbociclib. Additional work is required 
to explore the role of CDK 4/6 inhibitor therapy in patients that have acquired anti-estrogen 
resistance via ESR1 mutation.  
 
2.6 
Immunotherapy in HR+/HER2- Breast Cancer 
 
The emergence of immune therapy has revolutionized the treatment of multiple tumor types. Novel 
agents including the checkpoint inhibitors that impact PD-1 and PD-L1 signaling have been 
approved in multiple malignancies including melanoma, non-small cell lung cancer, and bladder 
cancer, with impressive results to date in other malignancies including various lymphomas, GI 
cancer, and squamous cell carcinoma of the head and neck. To date, early results with immune 
checkpoint blockade in breast cancer have been mixed. The majority of early clinical studies have 
incorporated single agent PD-1 or PD-L1 in the triple negative breast cancer population. This is 
based, in part, upon the knowledge that at least a subset of patients with triple negative breast 
cancer harbor a genomic signature enriched in immunomodulatory effectors47). Patients with triple 
negative breast cancer also seem to express higher relative levels of PD-L1 compared to non-triple 
negative controls48.  
 
Phase I studies of the PD-1 inhibitor pembrolizumab and the PD-L1 inhibitor atezolizumab have 
been reported in triple negative breast cancer49. Both of these studies reported overall response 
rates of approximately 18-19%, with a subset of durable, long-term responders. Limited experience 
exists to date in the HR+ breast cancer population though, per the Keynote 028 phase I study, PD-
1 checkpoint blockade was well tolerated in the endocrine-resistant breast cancer population (Rugo 
HS SABCS 2015). The novel PD-L1 inhibitor avelumab, discussed in detail below, was assessed 
in a mixed population of patients with metastatic breast cancer in the phase I setting (Dirix SABC 
2015). In this study, which included nearly 170 patients with up to three lines of prior 
chemotherapy, avelumab was well tolerated. The overall response rate was approximately 5%, 
with a range from 3% (in ER+/HER2- patients) to 9% (in triple negative patients). More than 20% 
of the patients on this study achieved stable disease. It is important to acknowledge that broad 
generalizations regarding the utility of immune therapy in breast cancer are hampered by relatively 
small sample sizes, differences amongst patient populations in the various studies, divergent 
inclusion criteria (including PD-L1 positivity), and arbitrary cut-points for PD-L1 expression. A 
larger study in a uniform population of HR+/HER2- metastatic breast cancer patients is needed to 
better assess the utility of PD-L1 blockade in the endocrine resistant population.   
 
2.7 
Avelumab Mechanism of Action 
 
Avelumab (also referred to as MSB0010718C) is a fully human IgG1 antibody directed against 
PD-L1. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 

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and B7.1. This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, resulting in 
the restoration of cytotoxic T cell response.  
 
The PD-1 receptor is expressed on activated CD4+ and CD8+ T cells. By interaction with its 
ligands, PD-L1 and PD-L2, PD-1 delivers a series of strong inhibitory signals through its 
cytoplasmic tail to inhibit T cell functions52-54. PD-L1 (also called B7-H1 and CD274) can be 
detected on resting and activated T cells, B cells, macrophages, dendritic cells, and mast cells; PD-
L1 expression is greatly up-regulated after activation or interferon treatment53.Numerous results 
from in vitro cellular assays have demonstrated that blockade of the PD-1/PD-L1 interaction 
enhances T cell responses, such as increases in proliferation and cytokine production55-61.In PD-
1–/–mice both T and/or B cells responses are unregulated resulting in an array of autoimmune 
pathologies62,63. Breaking tolerance through blocking PD-1 interaction with its ligands, and thus 
PD-1 signaling, can be applied to enhance Tcell activity towards chronic pathologies such as 
cancer64.  
 
External63and internal immunohistochemistry studies have demonstrated that PD-L1 is also 
expressed by a variety of human tumors, both by the tumor cells, as well as by the immune cells 
that are present in the tumor microenvironment. In contrast to very strong expression on 
syncytiotrophoblasts in the placenta and in cancer cells, low levels of PD-L1 expression were 
detected in some normal tissues including fetal cardiac tissue58. High levels of PD-L1 expression 
have been found to be associated with disease progression, increased metastasis, poor response to 
treatment, and decreased survival in a number of human cancers63. Importantly anti-PD-L1 
blockade has demonstrated therapeutic efficacy in a variety of murine tumor models as 
monotherapy and has shown synergistic effect in combination therapy setting56, 65-70.  
 
The antitumor activity of avelumab has been investigated in various murine tumor models. 
Inhibition of the PD-1/PD-L1 interaction is proposed to exert a therapeutic effect by restoring anti-
tumor CD8+ T cell responses.  
 
To circumvent the need for a surrogate antibody, the lead candidate antibody was specifically 
selected for cross-reactivity to murine PD-L1, and, as consequence all of the nonclinical studies 
were conducted in syngeneic murine tumor models in which the immune system of the host is fully 
intact. It was demonstrated that the inhibition of the PD-1/PD-L1 interaction restores anti-tumor 
CD8+ T cell responses, which results in an anti-tumor activity.  
 
Avelumab has demonstrated significant nonclinical activity as a monotherapy and in various 
combination therapy settings. In general, the anti-tumor immunotherapy via blockade of the PD-
1/PD-L1 axis seems not to be limited to any specific tumor types, but there is recent evidence that 
PD-L1 tumor expression is a pre-requisite to achieve an objective response upon blockade of the 
PD-1/PD-L1 axis71. The clinical relevance of PD-1/PD-L1 blockade has been demonstrated in 
Phase I trials performed with antibodies targeting either PD-L1 or PD-171, 72.  
 
Given the important role of PD-L1 in the suppression of T-cell responses, and the mode of action 
of avelumab which blocks the interaction between PD-L1 and its receptors, avelumab is being 
developed as a potential therapy for subjects with various tumors. 
 

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Clinical Phase I/II trials with MoAbs targeting either PD-L1 or PD-1 have shown promising hints 
for clinical efficacy, i.e., objective tumor response in indications such as NSCLC, melanoma, and 
ovarian cancer71-73.  
 
Avelumab has 2 main mechanisms of action for exerting its anti-tumor effects:   
 
• PD-L1 on tumor cells can interact with PD-1 or B7-1 on activated T cells. These interactions 
have been shown to significantly inhibit T cell activities. Therefore, blocking PD-L1 
interaction with PD-1 or B7-1 by anti-PD-L1 can release T cells from immunosuppression, 
and lead to elimination of tumor cells by T cells.  
• Tumor cells may express high levels of PD-L1 on their surface compared with normal tissues. 
As a fully human IgG1 MoAb, avelumab has antibody-dependent cellular cytotoxicity 
(ADCC) potential. Upon binding to PD-L1 on tumor cells and binding with their Fcpart to Fc-
gamma receptors on leukocytes, avelumab can trigger tumor-directed ADCC.  
 
Therefore, blocking PD-L1 inhibitory mechanisms by interactions with not only PD-1 but also the 
other ligand, B7-1, avelumab offers unique therapeutic potential compared with MoAbs targeting 
PD-1. 
 
2.8 
Avelumab Pharmacokinetic Data and Dose Selection 
 
A dose of 10 mg/kg of avelumab, intravenous (Iv) once every 2 weeks, was selected for the 
expansion cohorts of Phase I trials, the Phase II pivotal trial (EMR100070-003),and the ongoing 
Phase III trials based on the preliminary pharmacokinetic(PK),target occupancy, and preliminary 
clinical safety data collected in the clinical trials.  
 
Avelumab plasma levels leading to full programmed death ligand 1 (PD-L1) receptor target 
occupancy (TO) on PBMCs resulted in tumor growth inhibition in a murine disease model. 
Therefore, full TO on PBMCs can be considered a PD marker for the ability of avelumab to act on 
its target and to show clinical activity. 
 
Preliminary PK data from EMR 100070-001 show that the concentration at the end of dose interval 
(Cmin) increased more than proportionally to dose between 1 to 10 mg/kg, but proportionally for 
doses above 10 mg/kg. Consistently the t1/2 also increased with the dose. However, the average 
value was 102 and 120 hours for 10 mg/kg and 20 mg/kg, respectively, with no significant 
difference between these two dose groups. This PK characteristic suggests that target mediated 
drug disposition is involved in the clearance of avelumab and a high PD-L1 TO is likely achieved 
at the trough concentration for doses of 10mg/kg and 20mg/kg.  
 
The in vitro target occupancy data further support that a high TO is likely achieved at 10 mg/kg 
and above.  
 
Target occupancy was measured ex vivo by flow cytometry on peripheral blood CD3+ T cells 
from patients (n=9) treated with avelumab. After the first dose of the initial dose-escalation portion 
of Trial EMR 100070-001, the observed mean target occupancy reached a plateau of about 90% 
on Day 15 pre-dose for dose levels of 3 mg/kg and above.  

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In addition, in vitro target occupancy was measured using flow cytometry on peripheral blood 
CD3+ T cells from 8 healthy volunteers after spiking avelumab over a concentration range of 0.003 
to 10 μg/mL. A 50% target occupancy was observed at a drug concentration (standard deviation 
[StD]) of 0.122 (0.042) μg/mL, and a concentration of 1 µg/mL avelumab was required for > 95% 
target occupancy. Based on these data and the trough serum levels observed in EMR 100070-001, 
target occupancy was projected to reach or exceed > 95% throughout the entire dosing interval for 
10/13 subjects at 3 mg/kg, and for all (15/15) subjects at 10 mg/kg group from dose escalation 
group in EMR1000700-001.  
 
Based on the ex-vivo peripheral blood CD3+ T cell and in vitro target occupancy results, the dose 
of 10 mg/kg every 2weeks is expected to achieve target saturation during the entire dosing interval 
in the majority of patients.  
 
As of the safety cutoff date of 05 November 2015, 1353 subjects have received at least 1 dose of 
avelumab at doses ranging from 1.0 to 20 mg/kg in the Phase I Trial EMR 100070-001, of which 
1315 have received the proposed dose of 10mg/kg (15 in the dose escalation part of the study and 
1300 subjects in the pooled expansion cohort).  
 
In the dose escalation portion of the Phase I study, there was no evidence of differences in the 
safety profile across all administered dose levels from 1 mg/kg to 20 mg/kg. The MTD was not 
reached. Ongoing review of the safety data by the Safety Monitoring Committee (SMC) suggests 
an acceptable safety profile of avelumab administered at the 10 mg/kg every 2 weeks dose and 
schedule. Treatment-related treatment-emergent adverse events (TEAEs) were observed in 813 
(62.5%) subjects in the pooled expansion cohort. The most frequently observed treatment related 
TEAEs (incidence > 5%) were fatigue (212 subjects, 16.3%), infusion-related reaction (209 
subjects, 16.1%), nausea (108 subjects, 8.3%), chills (102 subjects, 7.8%), diarrhea (79 subjects, 
6.1%), and pyrexia (72 subjects, 5.5%).Grade ≥ 3 treatment-related TEAEs were observed in 124 
subjects (9.5%) in the pooled expansion cohort. The most frequently reported Grade ≥ 3 treatment 
related TEAEs were gamma-glutamyl transferase increased (GGT) and infusion-related reaction 
(each occurred in 9 subjects; 0.7%). Infusion-related reactions including drug hypersensitivity 
reactions and immune-mediated adverse reactions have been identified as expected adverse drug 
reactions of avelumab. The safety profile of avelumab is consistent with findings reported for other 
anti-PD-1 or anti-PD-L1 antibodies. 
 
In conclusion, preliminary data from EMR 100070-001 showed that avelumab at doses up to 
20mg/kg Iv every 2 weeks was well tolerated, and the dose of 10 mg/kg Iv every 2 weeks was 
considered to have an acceptable safety profile for further investigation in clinical studies. 
 
2.9 
Avelumab Clinical Data 
 
Avelumab is currently in clinical development across Phases I, II, and III. These include:  
 
• EMR 100070-001: A Phase I, open-label, multiple ascending dose trial to investigate the 
safety, tolerability, pharmacokinetics, biological and clinical activity of avelumab in subjects 
with metastatic or locally advanced solid tumors and expansion to selected indications  

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• EMR 100070-002: A Phase I trial to investigate the tolerability, safety, pharmacokinetics, 
biological and clinical activity of avelumab in Japanese subjects with metastatic or locally 
advanced solid tumors, with expansion part in Asian subjects with gastric cancer  
• EMR 100070-003: A Phase II, single arm, open-label, multicenter trial to investigate the 
clinical activity and safety of avelumab in subjects with Merkel cell carcinoma(MCC)  
• EMR 100070-004: A Phase III open-label, multicenter trial of avelumab versus docetaxel in 
subjects with non-small cell lung cancer that has progressed after a platinum-containing 
doublet  
 
EMR 100070-001 is a Phase I, open-label, multiple ascending dose trial to investigate the safety, 
tolerability, PK, biological and clinical activity of avelumab in subjects with metastatic or locally 
advanced solid tumors and expansion to selected indications. This trial consists of 2 parts. In the 
dose escalation part, sequential cohorts of subjects were enrolled at progressively higher dose 
levels (ranging from 1.0, 3.0, 10.0, and 20.0 mg/kg once every 2 weeks) with a 3 + 3 algorithm 
design for determination of the maximum tolerated dose (MTD) of avelumab; in the treatment 
expansion phase, subjects in different tumor cohorts are being treated with 10 mg/kg of avelumab 
once every 2 weeks until, confirmed progression, unacceptable toxicity, or any reason for 
withdrawal occurs. More than 1500subjects have been enrolled in the EMR100070-001 trial. The 
3 + 3 dose escalation algorithm to determine the MTD is complete and a dose of 10 mg/kg once 
every 2 weeks was determined for the tumor expansion cohorts on the basis of safety, PK, and PD 
observations. The treatment expansion part of the trial consists of 16tumor treatment cohorts. As 
of 05 November 2015 (data cutoff for a pre-planned safety data review by the study Safety 
Monitoring Committee [SMC]), 53 subjects in the dose escalation part had received avelumab (4, 
13, 15, and 21 subjects had received 1.0, 3.0, 10.0, and 20.0mg/kg of avelumab, respectively) and 
1300 subjects in the pooled expansion part had received 10 mg/kg avelumab and were followed 
up for at least 4weeks. 
 
The safety summary summarizes data from 1300subjects treated in the pooled treatment expansion 
cohort from the ongoing Phase I Trial EMR100070-001 (as of 05 November 2015). The pooled 
data included subjects treated in all tumor expansion cohorts, including non-small cell lung cancer 
(NSCLC), metastatic gastric cancer, breast cancer, colorectal cancer, castrate-resistant prostate 
cancer, adrenocortical carcinoma, melanoma, mesothelioma, urothelial carcinoma, ovarian cancer, 
renal cell carcinoma, and squamous cell cancer of the head and neck. Safety data are also 
summarized for 52 subjects in the ongoing Phase I Trial EMR 100070-002 and for 88 subjects in 
the ongoing Phase II Trial EMR100070-003 (as of 17December 2015). For TrialEMR100070-004, 
an overview of the serious adverse events (SAEs) is provided. 
 
Most of the observed adverse events (AEs) were either in line with those expected in subjects 
with advanced solid tumors or with class effects of monoclonal antibody (mAb) blocking the 
PD-1/PD-L1 axis. Infusion-related reactions including drug hypersensitivity reactions and 
immune-mediated adverse reactions (immune-related pneumonitis, immune-related colitis, 
immune-related hepatitis, immune-related endocrinopathies (thyroid disorders, adrenal 
insufficiency, new onset type I diabetes mellitus, pituitary disorders), immune-related nephritis 
and renal dysfunction and other immune-related AEs (myositis, myocarditis, Guillain-Barré 
syndrome, uveitis, pancreatitis). Guidelines for the management of immune-mediated adverse 

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reactions and infusion-related reactions are implemented in all ongoing clinical studies with 
avelumab. 
 
The clinical efficacy information summarized in the Investigator’s Brochure includes data from 
the following expansion cohorts of the ongoing Phase I TrialEMR100070-001, NSCLC (second 
line and first line cohorts), ovarian cancer, GC/GEJ, UC, mesothelioma, and adrenocortical 
carcinoma. In addition, efficacy results for 20 subjects in the gastric cancer expansion cohort of 
the ongoing Phase I Trial EMR 100070-002 and 88 subjects in Part A of the ongoing Phase 1 
Trial EMR 100070-003 in mMCC are summarized.  
 
The NSCLC expansion cohort in the ongoing Phase I Trial EMR100070-001 had a cutoff date of 
15 January 2015, 6 months after start of avelumab treatment of the last subject in this expansion 
cohort (a total of 184 treated subjects). The objective response rate (ORR) based on confirmed and 
unconfirmed responses for subjects treated in the NSCLC expansion cohort was 14.1% (26 of 184 
NSCLC subjects). Progression free survival (PFS) and overall survival (OS) were all evaluated for 
all NSCLC subjects treated in the expansion phase. As of 15 January 2015, the median PFS and 
OS for the NSCLC treatment expansion cohort were 11.6 weeks and 8.4 months, respectively. 
 
The clinical activity of avelumab was also evaluated by subjects’ tumor PD-L1 expression status 
in the NSCLC expansion cohort. An objective response was observed in 20 of 122 subjects 
(16.4%) who were PD-L1 positive (defined as having at least 1% PD-L1 positive tumor cells) 
compared with 2 of 20 subjects (10.0%) who were considered PD-L1 negative (defined as having 
less than 1% PD-L1 positive tumor cells). A longer median PFS (12.0vs 5.9 weeks) and OS (8.9 
vs 4.6months) were both observed in PD-L1 positive compared with PD-L1 negative subjects. 
 
The ovarian cancer expansion cohort had a data cutoff of 13 February 2015, approximately 13 
weeks after the start of avelumab treatment on the last subject who was included in this pre-planned 
interim analysis on this expansion cohort. The ORR based on confirmed and unconfirmed 
responses for subjects treated in the ovarian cancer expansion cohort was 10.7% (8 of 75 subjects). 
The median PFS for the ovarian cancer expansion cohort was 11.4 weeks (95%confidence interval 
(CI): 6.3 to 12.0weeks). 
 
The preliminary efficacy data for the ongoing Phase I Trial EMR 100070-002 are based on a data 
cutoff of 11 March 2015. As of the data cutoff, 3 of 20 subjects responded to trial treatment (all 
responses were partial responses [PRs] and all responses were confirmed responses), and the best 
overall response (BOR) was 15.0% (95%CI: 3.2%to 37.9%). The median PFS of this group was 
11.9 weeks (95% CI: 6.0 to 12.3weeks). 
 
Avelumab was approved by the FDA in March 2017 for treatment of Merkel-cell carcinoma. 
 
The results of a Phase I cohort expansion trial in patients with metastatic breast cancer were 
presented at the 2015 San Antonio Breast Cancer meeting (Dirix et al, SABCS 2015).  In this trial, 
168 patients with metastatic breast cancer with up to 3 prior lines of therapy in the metastatic 
setting were treated with avelumab 10 mg/kg every 2 weeks until disease progression. Overall, 
treatment was well tolerated, with the primary grade >3 clinically significant toxicities 

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including autoimmune hepatitis (3 patients, 1.8%), GGT increase (3 patients, 1.8%) and fatigue (3 
patients, 1.8%). Eight patients (4.8%) experienced grade 1/2 hypothyroidism, and one patient each 
experienced grade 3 pneumonitis, or grade 4 thrombocytopenia. The overall response rate in this 
unselected population was 4.8% (95% CI 2.1, 9.2) with one complete and 7 partial responses. An 
additional 23.2% of patients had stable disease. The median time to response was 11.4 weeks 
(range, 5.7-17.7 weeks), the median duration of response was 28.7 weeks (95% CI: 6.1, ne), and 
responses were ongoing in 5/8 patients at time of the analysis. Tumor shrinkage of ≥30% was 
observed in 16 patients (9.5%), including 2 patients with progressive disease by RECIST who had 
partial responses by modified Immune RECIST Criteria (irRC). Responses were seen in all 
molecular subtypes. PD-L1 status in 136 evaluable patients did not appear to correlate with 
response, although small numbers and varying cut-offs make this data difficult to interpret.  
 
Response rates of ER-positive breast cancers to immune checkpoint blockade agents (e.g. anti-
PD1 therapy) have been limited in clinical trials reported so far. This is likely because ER-positive 
breast cancers generally show low rates of lymphocytic infiltration and/or because they do not 
present a significant antigenic load to cytotoxic T cells. Possible strategies to increase the 
susceptibility of ER-positive breast cancers to immunotherapy thus include those that increase T 
cell activity within these tumors, or those that increase the “antigenicity” of tumor cells. 
Preliminary lab data suggests that the combination of CDK4/6 inhibition and anti-PD1 therapy is 
more effective than either monotherapy alone, and that this effect is potentially mediated by one 
or both of these mechanisms76. 
 
2.10 
Rationale 
 
Palbociclib has an established role in the treatment of metastatic HR+/HER2- breast cancer, both 
in the first-line setting (in combination with an aromatase inhibitor) as well as in patients who have 
been previously treated with endocrine therapy (in combination with fulvestrant). The combination 
of antihormonal therapy with the CDK4/6 inhibitor palbociclib has emerged as the FDA-approved 
standard of care for patients with metastatic HR+/HER2- breast cancer based upon the results of 
the PALOMA-1 and PALOMA-3 studies. The mechanisms governing resistance to these regimens 
(both de novo and acquired) remain poorly understood. The therapeutic paradigm of continuation 
of target blockade beyond progression is pursued in anti-estrogen and anti-HER2 approaches for 
breast cancer, but it is not clear if continuation of palbociclib beyond prior progression on a 
CDK4/6 containing regimen is of clinical value as well. Furthermore, the role of immune therapy 
and checkpoint blockade following the development of CDK inhibitor resistance has not yet been 
explored. Given the expanding patient population that has developed resistance to the combination 
of anti-estrogen therapy and CDK 4/6 blockade, we set out to assess both of these questions in this 
clinical protocol. 
 
As outlined above, early data has implicated the loss of Rb in the development of resistance to 
CDK 4/6 inhibition. Upregulation of cyclin E via various signal transduction cascades (including 
the PI3K/AKT/mTOR pathway) has also been observed. Activating events in the PI3K signal 
transduction pathway, as well as acquisition of ESR1 mutations, have been identified as putative 
factors in the development of resistance to endocrine therapy. How these alterations, as well as 
previously unidentified mechanisms, might impact the development of clinical resistance 
constitutes an important exploratory endpoint of the current study. Additional tumor- or host-

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specific factors, such as intratumoral heterogeneity and genomic instability, might also impact the 
rate at which resistance develops, the magnitude of benefit gleaned by the application of ongoing 
CDK 4/6 blockade, and response to immune checkpoint blockade.  
 
As widespread use of CDK 4/6 inhibitors continues in the clinical arena, elucidation of the 
biologically-relevant mechanisms leading to resistance constitutes a critically important problem 
for investigation in the clinical trial setting. Insight into factors leading to progression on these 
regimens will assist in the development of rational second- and third-line approaches for the large 
group of patients receiving therapy for metastatic HR+/HER2- breast cancer.  
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
 
3.1.1 Participants must have histologically confirmed hormone receptor positive (HR+) 
HER2 negative metastatic or locally recurrent unresectable invasive breast cancer. Both 
measurable and non-measurable disease are allowed. ER, PR and HER2 measurements 
should be performed according to institutional guidelines, in a CLIA-approved setting. 
Cut-off values for positive/negative staining should be in accordance with current 
ASCO/CAP (American Society of Clinical Oncology/College of American 
Pathologists) guidelines. 
 
3.1.2 Men and pre- and postmenopausal women are eligible.  Ongoing monthly GNRH 
agonist is required in pre-menopausal women or male participants for at least 4 weeks 
prior to study entry. 
 
3.1.3 Participants must have radiological or objective evidence of progression on an 
endocrine and CDK 4/6 inhibitor regimen in the metastatic setting, and/or 
relapse/progression during or within 12 months of completion of an endocrine and 
CDK4/6 inhibitor regimen in the adjuvant setting. 
• Participants must have previously been exposed to CDK4/6 inhibitor therapy in 
combination with endocrine therapy. Exposure to any prior CDK4/6 inhibitor, 
(including palbociclib, abemaciclib, and ribociclib) is allowed. Patients may have a line 
of endocrine therapy after combination endocrine and CDK4/6 inhibitor exposure. 
• Participants must have remained on prior endocrine and CDK4/6 therapy in the 
metastatic setting without progression for at least 6 months prior to study entry. 
• It is not mandatory to have a CDK 4/6 inhibitor containing regimen as the most recent 
treatment. 
• Participants may have had no more than 1 prior line of endocrine and CDK4/6 inhibitor 
therapy in the metastatic setting  
 
3.1.4 Participants may have 0-1 prior lines of cytotoxic chemotherapy in the metastatic 
setting. 
 

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3.1.5 Prior endocrine therapy in the metastatic setting may include any aromatase inhibitor 
(AI) or tamoxifen. In the metastatic setting, 1-2 prior lines of endocrine therapy are 
allowed. Prior Fulvestrant is permitted if the participant received <2 doses without 
concurrent endocrine therapy prior to enrollment and without evidence of disease 
progression. 
 
3.1.6 Participants may have received radiotherapy for palliative purpose, but must not be 
experiencing > grade 1 treatment related toxicities and must have completed treatment 
> 14 days prior to registration. 
 
3.1.7 Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of study agents in participants <18 years of age, children are excluded from this 
study. 
 
3.1.8 ECOG performance status 0-1 (see Appendix A). 
 
3.1.9 Participants must have normal organ and marrow function as defined below: 
• Absolute neutrophil count > 1,500/µL 
• Platelets > 100,000/µL 
• Hemoglobin > 9g/dL 
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN)  
• AST (SGOT)/ALT (SGPT) < 2.5 x institutional ULN, or ≤ 5 x ULN for subjects with 
documented metastatic disease to the liver. 
• Creatinine < institutional ULN or creatinine clearance > 30 mL/min/1.73 m2 for 
subjects with creatinine levels above institutional ULN. 
 
3.1.10 Women of childbearing age, women who are made postmenopausal through use of 
GNRH agonists, and men must agree to use adequate contraception for the duration of 
protocol treatment and for at least 90 days after the last dose of palbociclib if the risk of 
contraception exists.  
 
Adequate contraception is defined as one highly effective non-hormonal form of 
contraception or two effective forms of non-hormonal contraception by the participant 
and/or partner.  
 
Highly Effective Non-Hormonal Contraception 
Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly are considered highly-effective forms of contraception. 
The following non-hormonal methods of contraception are acceptable: 
• True abstinence when this is in line with the preferred and usual lifestyle of the 
participant. [Periodic abstinence (e.g., calendar, ovulation, symptothermal post-
ovulation methods) and withdrawal are not acceptable methods of contraception]. 
• Male sterilization (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female participants, the vasectomized male partner should 
be the sole partner. 
 

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OR 
 
 
Effective Non-Hormonal Contraception 
Alternatively two of the following effective forms of contraception may be used instead: 
• Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS). 
Consideration should be given to the type of device being used, as there is higher failure 
rates quoted for certain types, e.g., steel or copper wire. 
• Condom with spermicidal foam/gel/film/cream/suppository. 
• Occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/suppository. 
• The use of barrier contraceptives should always be supplemented with the use of 
spermicide. The following should be noted: 
• Failure rates indicate that, when used alone, the diaphragm and condom are not highly 
effective forms of contraception. Therefore, the use of additional spermicides does 
confer additional theoretical contraceptive protection. 
• However, spermicides alone are ineffective at preventing pregnancy when the whole 
ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception 
and should not be used alone. 
 
It should be noted that two forms of effective contraception are required. A double barrier 
method is acceptable, which is defined as condom and occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 
 
3.1.11 Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy 
testing does not need to be pursued in female participants who are: 
• Age > 60 years; or 
• Age < 60 with intact uterus and amenorrhea for 12 consecutive months or more AND 
estrogen (estradiol) levels within postmenopausal range; or 
• Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. 
 
3.1.12 Participant must be able to swallow and retain oral medication. 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
 
3.2.1 Participants who have had endocrine, chemotherapy, and/or biologic therapy < 7 days 
(other than fulvestrant) prior to entering the study or those who have not recovered from 
any prior treatment-related toxicities (must recover to no more than grade 1. Alopecia, 
sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 toxicity not constituting a safety risk 
based on investigator’s judgment are acceptable). 
 
3.2.2 Participants who have had prior therapy with any anti-PD-1, anti-PD-L1, L2, or anti-

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CTLA4 immunotherapy  
 
3.2.3 Participants who are receiving concurrent therapy with other investigational agents. 
 
3.2.4 Rapidly progressive, symptomatic, visceral spread of disease placing participant at risk 
of life-threatening complications in the short term. 
 
3.2.5 Participants with active brain metastases. Stable treated brain metastases are allowed 
(this includes participants who have documented radiologic stability at least 4 weeks 
after radiotherapy, and do not require systemic steroids for management of symptoms 
from CNS metastatic lesions). 
 
3.2.6 Participants who have discontinued prior palbociclib for toxicity, or have needed more 
than two dose reductions for toxicity from prior palbociclib therapy. If a participant 
previously required dose reductions during prior palbociclib therapy and tolerated it 
well, for example prior dosing at 100 mg or 75 mg qd 3 weeks on 1 week off schedule, 
then that dose may be selected for this trial. 
 
3.2.7 History of allergic reactions to palbociclib or attributed to compounds of similar 
chemical or biologic composition to palbociclib. 
 
3.2.8 Known prior severe hypersensitivity to investigational product or any component in its 
formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v4.03 Grade ≥ 3) 
 
3.2.9 Participants receiving any medications or substances that are strong inhibitors or 
inducers of CYP3A isoenzymes are ineligible. Lists including medications and 
substances known or with the potential to interact with the CYP3A isoenzymes are 
provided in Appendix B, and can also be found within Section 5.4.  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.   
 
3.2.10 Prior organ transplantation including allogenic stem-cell transplantation  
 
3.2.11 Current use of immunosuppressive medication, except for the following: a. intranasal, 
inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. 
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication). 
 
3.2.12 Uncontrolled intercurrent illness including, but not limited to: ongoing or active 

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infection requiring systemic therapy, clinically significant cardiovascular disease 
including: cerebral vascular accident/stroke (< 6 months prior to enrollment), 
myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive 
heart failure (≥ New York Heart Association Classification Class II), or serious cardiac 
arrhythmia requiring medication, uncontrolled diabetes mellitus, or psychiatric 
illness/social situations that would limit compliance with study requirements.  Ability 
to comply with study requirements is to be assessed by each investigator at the time 
of screening for study participation. 
 
3.2.13 Active autoimmune disease that might deteriorate when receiving an immuno-
stimulatory agent.  Participants with diabetes type I, vitiligo, psoriasis, or hypo- or 
hyperthyroid diseases not requiring immunosuppressive treatment are eligible. 
 
3.2.14 Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome, or need to receive combination antiretroviral therapy for HIV 
 
3.2.15 Known history of colitis, inflammatory bowel disease, pneumonitis, or pulmonary 
fibrosis.  
 
3.2.16 Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) 
 
3.2.17 Live vaccination within 4 weeks of the first dose of avelumab  
 
3.2.18 Pregnant women are excluded from this study because effect of palbociclib and 
avelumab on a developing fetus is unknown. Breastfeeding should be discontinued prior 
to entry onto the study. 
 
3.2.19 Individuals with a history of a different malignancy are ineligible except for the 
following circumstances. Individuals with a history of other malignancies are eligible if 
they have been disease-free for at least 3 years and are deemed by the investigator to be 
at low risk for recurrence of that malignancy. Individuals with the following cancers are 
eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the 
breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
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 

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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 and DF/PCC 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 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Project Manager.  All sites should email or call the Project Manager to verify slot availability.  
The required forms in Section 4.4 should be emailed or faxed to the Project Manager.  
 
Following registration, participants should begin protocol therapy within 7 business days. Issues 
that would cause treatment delays should be discussed with the Overall PI.  If a participant does 
not receive protocol therapy following registration, the participant’s registration on the study 
must be canceled.  The Project Manager should be notified of cancellations as soon as possible. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the research nurse or 
data manager and emailed to the Project Manager at CTOPM@dfci.harvard.edu or faxed to 617-
632-5152: 
• Clinic visit note documenting history and physical exam 
• Copy of required laboratory tests including: Hematology (CBC with differential), serum 
chemistries (creatinine clearance, bilirubin, ALT, and AST), hepatitis testing, pregnancy 
testing if necessary.  
• Pathology report and documentation of ER/PR status and HER2 status.  
• ECG report 
• Signed participant consent form 
• HIPAA authorization form (if separate from the informed consent document) 
• Completed DF/HCC Eligibility Checklist with stratification  
  
To complete the registration process, the Project Manager will 
• follow the DF/HCC Standard Operating Procedure for Human Subject Research Titled 
Subject Protocol Registration (SOP #: REGIST-101) and register the participant on the 
protocol 

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• call or email the research nurse or data manager at the participating site with the 
participant study number, and to confirm registration 
 
NOTE: Registration can only be conducted during the business hours of 8:00 AM and 5:00 
PM Eastern Time Monday through Friday. Same day treatment registrations will only be 
accepted with prior notice and discussion with the DF/HCC Project Manager.  
 
5. TREATMENT PLAN 
 
Agents will be administered per the table below.  Cycles last 4 weeks (28 consecutive days) and 
the start of a cycle is defined as the day when palbociclib administration begins. Treatment will 
be administered on an outpatient basis. Expected toxicities and potential risks as well as dose 
modifications for study medications are described in Section 7 (Expected Toxicities and Dosing 
Delays/Dose Modification). No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant’s malignancy. 
 
5.1 
Treatment Regimen 
 
This is a phase II, randomized study of fulvestrant alone versus fulvestrant and palbociclib 
versus fulvestrant, palbociclib, and avelumab in patients with metastatic or locally 
advanced/unresectable HR+/HER2- breast cancer that have demonstrated prior progression on a 
combination of endocrine therapy + CDK 4/6 inhibitor. 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.  
 
Arm A: Fulvestrant Alone. Upon progression, patients may begin Palbociclib. 
Arm B: Fulvestrant, Palbociclib 
Arm C: Fulvestrant, Palbociclib, Avelumab 
 
Table 1. Treatment Description 
Treatment Description 
Agent 
Premedications/ 
Precautions 
Starting 
Dose 
Route 
Schedule 
Cycle Length 
Palbociclib 
Given with food 
 
125 mg* 
  
PO 
Daily on 
days 1-21, 
followed by 
one week off 
28 days 
(4 weeks) 
Fulvestrant 
N/A 
 500mg 
(two 
injections 
of 250 mg 
each) 
IM 
Cycle 1:  
Day 1, 15; 
 
Subsequent 
cycles: Day 1 

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Avelumab 
Premedicate with 
antihistamine and 
acetaminophen, 
or per local 
guidelines 
guidelines for the 
first 4 infusions.  
Premedication 
should be 
administered for 
subsequent 
avelumab doses 
based upon 
clinical judgment 
and presence/ 
severity of prior 
infusion 
reactions. This 
regimen may be 
modified based 
on local treatment 
standards and 
guidelines as 
appropriate; 
however, the 
prophylactic use  
of systemic 
corticosteroids is 
not permitted. 
10mg/kg 
IV 
Every 14 
days 
*Patients may continue at same dose if previously treated with palbociclib at 100 mg or 75 mg 
 
Day 1 of each cycle begins with fulvestrant dosing. 
 
5.2 
Pre-Treatment Criteria 
 
Informed consent will be obtained after the study has been fully explained to the subject and before 
the conduct of any screening procedures or assessments. If screening assessments occur within 
7 days before start of study treatment, then they may serve as the baseline Cycle 1 Day 1 study 
tests do not need to be repeated. 
Pre-treatment criteria will be assessed within 14 days of the first dose of study treatment to 
establish eligibility and baseline values.  This will be considered the baseline clinical evaluation.  
Additional pre-treatment evaluations, also found in Section 3.1.6, are CBC with differential, 
chemistries, and EKG.  Pregnancy testing for screening should be obtained in appropriate 
patients, as defined in Eligibility. Required results for initiation of protocol therapy include: 
 
• Absolute neutrophil count > 1000/µL 

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• Platelets > 100,000/µL 
• Hemoglobin > 9g/dL 
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN)  
• AST (SGOT)/ALT (SGPT) < 2.5 x institutional ULN, or AST and ALT levels ≤ 5 x ULN 
(for subjects with documented metastatic disease to the liver). 
• Creatinine < institutional ULN or creatinine clearance > 30 mL/min/1.73 m2 for subjects 
with creatinine levels above institutional ULN. 
• Baseline negative hepatitis testing (HBV sAg and anti HCV antibody) 
• Negative pregnancy test (in appropriate patients) 
• Thyroid testing with free T4 and TSH 
 
Refer to Section 6.2.1 for treatment parameters required after dose delays and re-treatment.  
 
5.3 
Agent Administration 
 
5.3.1 Palbociclib 
 
Palbociclib 125 mg should be taken orally, once per day, with food.  Patients who 
previously required a dose reduction of palbociclib to 100 or 75 mg daily and tolerated 
it well can begin with that dose. If a dose is vomited, a replacement dose should NOT 
be taken.  If a dose is missed, and it is less than 6 hours from usual time of dosing, 
then patients may take that dose. Otherwise that dose should be skipped and NOT 
retaken; patients should resume regular dosing the following day.  Patients who 
inadvertently take 1 extra dose during a day must skip the next day’s dose.  Treatment 
is continuous daily for 21 days, and then 7 days off, to complete a 28 day cycle. 
 
On days when patient is scheduled for a clinic visit, the patient may take palbociclib at 
home or in the clinic prior to addition investigational therapy.  
 
Patients will be required to return all bottles of palbociclib at each study visit for drug 
accountability.  The number of remaining capsules/tablets will be documented and 
recorded. 
 
5.3.2 Fulvestrant 
 
Fulvestrant 500 mg will be administered in the clinic as two IM injections of 250 mg each 
on Cycle 1 Days 1 and 15, and Day 1 of each subsequent 28-day (4-week) cycle. For 
participants who have had at least 1 dose of fulvestrant prior to enrollment, subsequent 
fulvestrant injections will administered on Day 1 of each 28-day cycle (no Day 15 dose).  
 
An administration window of +/- 2 days is allowable. Fulvestrant must be administered at 
the participating study site.  
 
For participants in Arm C, fulvestrant should be administered prior to avelumab infusion. 
For details regarding the dosing instructions and safety profile of fulvestrant, refer to the 
fulvestrant package insert or SmPC.   

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5.3.3 Avelumab 
 
Avelumab will be administered as10 mg/kg body weight IV once every 2 weeks. An 
administration window of +/- 2 days is allowable. For participants in Arm C, fulvestrant 
should be administered prior to avelumab infusion. Avelumab is administered as a 1-hour 
IV infusion, diluted with 0.9% saline solution. 
 
Premedication: In order to mitigate infusion-related reactions, a premedication with an 
antihistamine and with acetaminophen 30 to 60 minutes prior to the first 4 infusions of 
avelumab is mandatory (for example, 25-50 mg oral diphenhydramine and 500-650 mg 
oral acetaminophen).  Premedication should be administered for subsequent avelumab 
doses based upon clinical judgment and presence/severity of prior infusion reactions. This 
regimen may be modified based on local treatment standards and guidelines as appropriate; 
however the prophylactic use of systemic corticosteroids is not permitted.    
Setting: Avelumab should be administered in a setting that allows for immediate access 
to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications 
(IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access. 
Observation period:  Following avelumab infusions, patients must be observed for 30 
minutes post-infusion for potential infusion-related reactions.   
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
All prior treatment or medication administered during the 30 days preceding the first dose of study 
treatment and any concomitant therapy administered to the subject throughout the study until 
30 days after the final dose of study treatment must be recorded on the Prior and Concomitant 
Therapy page of the eCRF. The generic name of the drug (or trade name for combination drugs) 
must be specified along with the duration of treatment and indication for use. If concomitant 
medication/therapy is administered for an adverse event (AE), investigators will record that AE on 
the AE page of the eCRF. 
Supportive care medications are allowed at any time on trial.  Specifically, the following agents 
are permitted: 
• Antiemetics 
• Antidiarrheal therapy 
• Antiallergic measures such as corticosteroids and antihistamines 
• 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. 

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• Agents to assist in management of endocrine therapy-induced side effects (NSAIDs, 
gabapentin, duloxetine, venlafaxine, citalopram, etc) 
 
Growth factors, including GCSF, are not allowed on trial. The use of concurrent investigational or 
other antitumor therapies, other than endocrine therapy, is not permitted. Concurrent palliative 
radiotherapy is not allowed on trial, except in circumstances when the need for radiotherapy does 
not reflect progressive disease. If radiotherapy is necessary, all agents except for fulvestrant should 
be held during radiation.  
 
Strong CYP3A inhibitors/inducers are not allowed on study.  Palbociclib is metabolized to 
multiple metabolites in a qualitatively similar manner in rat, dog and human liver microsomes.  In 
vitro, Palbociclib is primarily metabolized by CYP3A4 enzymes.  Co-administration with drugs 
that are CYP3A inhibitors and inducers may change the plasma concentrations of palbociclib in 
humans.  The concurrent use of CYP3A inhibitors, including amprenavir, atazanavir, boceprevir, 
clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and 
grapefruit, grapefruit juice or any product containing grapefruit, are not allowed in the study.  The 
concurrent use of CYP3A inducers, including carbamazepine, felbamate, nevirapine, 
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. 
Patients taking proton pump inhibitors must take palbociclib capsules with food. The new tablet 
formulation of palbociclib may be taken with or without food and can be taken with proton pump 
inhibitors (PPI)/antacids. 
Chronic immunosuppressive therapies should be avoided, including systemic corticosteroids.  
Steroids given for physiological replacement, as anti-emetics or inhaled as well as short course 
of oral/topical steroids given for allergic reactions or asthma flares are allowed. 
The use of herbal medicine is not recommended during protocol treatment. 
Surgery is allowed during protocol therapy, however it is suggested to avoid nadir of counts at 
time of surgery. Patients pursuing surgery must hold palbociclib (and avelumab if in Arm C) 
therapy 7 days before the surgery and up to 2 weeks after surgery. Patients may resume palbociclib 
(avelumab if in Arm C) therapy once satisfactory wound healing and recovery have occurred. 
Patients should continue endocrine therapy if other agents are held for surgery. 
 
5.4.1 Timing and use of contraception 
 

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The effects of palbociclib and avelumab on the developing human fetus are unknown.  If, for any 
reason, a woman should become pregnant or suspect that she is pregnant while participating in 
this study, she should inform her treating physician immediately.  
 
Females of childbearing potential, women who are made postmenopausal through use of GNRH 
agonists, and men should use adequate contraceptive methods during therapy and for at least 90 
days after last dose of palbociclib. Adequate contraception is defined as one highly effective 
non-hormonal form of contraception or two effective forms of non-hormonal contraception by 
the patient and/or partner. 
 
Highly Effective Non-Hormonal Contraception 
Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly are considered highly-effective forms of contraception. 
The following non-hormonal methods of contraception are acceptable: 
• True abstinence when this is in line with the preferred and usual lifestyle of the 
participant. [Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation 
methods) and withdrawal are not acceptable methods of contraception]. 
• Male sterilization (with appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate). For female participants, the vasectomized male partner should be 
the sole partner. 
 
Effective Non-Hormonal Contraception 
Alternatively two of the following effective forms of contraception may be used instead: 
• Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS). 
Consideration should be given to the type of device being used, as there is higher failure 
rates quoted for certain types, e.g., steel or copper wire. 
• Condom with spermicidal foam/gel/film/cream/suppository. 
• Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. 
• The use of barrier contraceptives should always be supplemented with the use of 
spermicide. The following should be noted: 
• Failure rates indicate that, when used alone, the diaphragm and condom are not highly 
effective forms of contraception. Therefore, the use of additional spermicides does confer 
additional theoretical contraceptive protection. 
• However, spermicides alone are ineffective at preventing pregnancy when the whole 
ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and 
should not be used alone. 
 
It should be noted that two forms of effective contraception are required. A double barrier 
method is acceptable, which is defined as condom and occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream /suppository. 
 
5.5 
Crossover Therapy 
 
For patients on Arm A, fulvestrant alone, patients may cross over to palbociclib monotherapy 
at time of confirmed disease progression. Decision on crossover will be made at the discretion 

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of the patient and provider.  Treatment may continue until one of the criteria listed in Section 
5.6. 
 
5.6 
Criteria for Removal from Treatment 
 
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: 
 
• Progression/Relapse based on RECIST 1.1 
• Progression/Relapse NOT based on RECIST 1.1, but with need to change systemic 
therapy  
• Intercurrent illness that prevents further administration of combination treatment, 
• Unacceptable toxicity to protocol therapy, 
• Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements, as determined by the treating provider 
• Participant decides to withdraw consent from the protocol therapy 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator (physician 
discretion). 
• Death 
 
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 case report form (CRF).  
 
If a patient discontinued study therapy due to toxicity, tumor assessments will continue to be 
performed at a minimum of 12-week intervals throughout long-term follow-up until documented 
disease progression, death, or withdrawal of consent. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator Erica L. Mayer MD MPH at 617-632-2335. 
 
5.7 
Follow Up 
 
Participants in Arms A or B will be followed for safety follow-up for 30 days after removal 
from protocol therapy or until death, whichever occurs first. For Arm C patients (Fulvestrant, 
Palbociclib, and Avelumab), given the potential risk for delayed immune-related toxicities, safety 
follow-up must be performed at least 90 days after the last dose of avelumab administration. The 
extended safety follow-up beyond 30 days after last study drug administration may be performed 
either via a site visit or via a telephone call with subsequent site visit requested in case any concerns 
noted during the telephone call. SAEs which occur after occur any time after the 30-day or 90-day 
period, respectively, will be followed to resolution if the Principal Investigator suspects a causal 
relationship between palbociclib or avelumab and the SAE. 
 
If a patient discontinued study therapy for reason other than disease progression, tumor 

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assessments will continue to be performed at a minimum of 12-week intervals throughout long-
term follow-up until documented disease progression, death, or withdrawal of consent. 
 
At time of disease progression, patients will be followed for survival at least every 6 months until 
time of death or withdrawal of consent. This will occur via telephone call if the site is unable to 
confirm status via chart review. If a patient withdraws consent to follow-up, attempts should be 
made to contact the patient to determine the reason for discontinuation. 
 
Subsequent anti-cancer medications, including dose and regimen, or cancer-related radiotherapy 
or cancer-related surgery since end of study treatment will be collected and recorded in the CRF 
for all patients, regardless of reason for treatment discontinuation.  
 
A subject who has ceased to return for visits will be followed up by mail, phone, or other means 
as much as possible to gather information such as the reason for failure to return and the status of 
treatment compliance, presence or absence of AEs, the clinical course of signs and symptoms, and 
survival. 
  
The end of study (EOS) will occur as of the date of the last visit of the last patient undergoing the 
study. In the event that the EOS is declared earlier, investigational product(s) will be available to 
patients who continue to receive clinical benefit. 
 
The reason for taking a participant off-treatment and off-study, and the date the participant was 
removed, must be documented in the case report form (CRF). 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  See Appendix D 
for an overview of CTCAE. 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until 30 days (90 days for Arm C) after removal from study 
or death, whichever occurs first. Participants continuing to experience toxicity at the off protocol 
therapy visit may be contacted for additional assessments until the toxicity has resolved or is 
deemed irreversible. 
 
In the event of significant treatment-related toxicity, dosing may be interrupted or delayed and/or 
reduced as described below. If treatment is held for toxicity, study assessments should stay on 
schedule according to the required data table.  In the event of multiple toxicities, dose 
modification should be based on the worst toxicity observed.  Patients are to be instructed to 
notify Investigators at the first occurrence of any adverse sign or symptom. 
6.1 
Palbociclib 
 

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6.1.1 Palbociclib Toxicity management 
 
Every effort should be made to administer study treatment on the planned dose and 
schedule. However, in the event of significant treatment-related toxicity, administration 
of palbociclib may need to be adjusted.  In the event treatment interruption is deemed 
necessary for palbociclib, treatment with the other medication(s) will continue as 
planned. 
 
As per Section 5.4, treatment with growth factors is not allowed on trial. 
 
If the retreatment parameters (see Section 6.1.3) are met within 3 weeks of treatment 
interruption or cycle delay, palbociclib may be resumed.  Please refer to Dose Reduction 
section for adverse events requiring dose reduction at the time of treatment resumption.  
If the retreatment parameters have not been met after 3 weeks of dose interruption 
(including the scheduled 1 week off treatment), the patient should permanently 
discontinue palbociclib treatment.  
 
For participants enrolled on Arm C, there is no required dose modification for palbociclib 
for grade 3 uncomplicated neutropenia at Day 15 after Cycle 2 [Cycle 3 and beyond].  
 
Patients holding palbociclib for surgery are allowed to hold 7 days before and up to 2 
weeks after surgery and are allowed to resume palbociclib therapy once satisfactory wound 
healing and recovery have occurred. Patients should continue fulvestrant and/or 
avelumab if palbociclib is held for surgery. 
 
Patients permanently discontinuing palbociclib treatment due to treatment-related toxicity 
should continue on fulvestrant and/or avelumab as per the investigator’s discretion and 
followed accordingly per protocol. 
 
6.1.2 Palbociclib Dosing Interruptions/Delays 
 
Patients experiencing the following adverse events should have their treatment of 
palbociclib interrupted/delayed until criteria for retreatment are met: 
• Uncomplicated Grade 3 or 4 neutropenia (ANC<1000/mm3); 
• Grade 3 or 4 neutropenia (ANC<1000/mm3) associated with a documented infection 
or fever 38.5C, 100.4F; 
• Platelet <75,000/mm3); 
• Grade 3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment); 
• Intolerable grade 2 non-hematologic toxicity persisting despite optimal medical 
treatment and lasting more than 3 weeks; 
• In case of concurrent > 3x ULN ALT and 2x ULN Total Bilirubin, palbociclib will be 
permanently discontinued.  
Patients should not hold or discontinue palbociclib for side effects potentially or likely 
related to concomitant fulvestrant therapy as per the investigator’s judgment. 

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Appropriate follow up assessments should be performed until adequate recovery occurs 
before treatment can resume. 
Missed doses are not made up. When the adverse event resolves, the cycle will continue 
as scheduled. 
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in Dose Reductions Section unless expressly agreed otherwise following 
discussion between the investigator and the sponsor.  If a dose reduction is applied, the 
patient may need to return to the clinic to receive new drug supply. 
6.1.3 Palbociclib Retreatment criteria 
 
Retreatment with palbociclib following treatment interruption for treatment related 
toxicity or at the start of any new cycle may not occur until all of the following 
parameters have been met: 
• Platelet count  75,000/mm3; 
• ANC  1000/mm3 and no fever; 
• Any persistent grade 3 or higher treatment-related non-hematologic AEs considered 
related to palbociclib have recovered to Grade ≤ 1 or baseline. 
 
If a treatment delay results from decline in hematologic parameters, the frequency of 
blood count assessments should be adjusted as clinically indicated. 
If the retreatment parameters are met within 3 weeks of treatment interruption or cycle 
delay, palbociclib may be resumed.  Please refer to Dose Reductions Section for adverse 
events requiring dose reduction at the time of treatment resumption.  
If these parameters have not been met after 3 weeks of dose interruption (including the 
scheduled 1 week off treatment), the patient should permanently discontinue palbociclib 
treatment.  
 
6.1.4 Palbociclib Dose Reductions 
 
Following dose interruption or cycle delay the palbociclib dose may need to be reduced 
when treatment is resumed. 
 
No specific dose adjustments are recommended for Grade 1 or short lasting Grade 2 (<3 
weeks) treatment-related toxicity. However, investigators should always manage their 
patients according to their medical judgment based on the particular clinical 
circumstances. 
 
Palbociclib will be dose reduced for treatment-related non-hematologic Grade 2 toxicity 
lasting for >3 weeks, despite optimal medical treatment. Palbociclib will be discontinued 
for subjects experiencing a persistent grade 2 treatment-related non-hematologic toxicity 
after 2 dose reductions, in the presence of maximum supportive care, as judged by the 

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investigator.  
 
Taking palbociclib according to recommendation (i.e., with food) should be reinforced 
and confirmed.  Dose reduction of palbociclib may be recommended depending on type 
and severity of the toxicity encountered (Table 2). Patients who start palbociclib therapy 
at 100mg (Dose level -1) or 75 mg (Dose level -2) can use the lower dose levels if dose 
reduction is necessary.  Once a dose has been reduced for a given patient, all subsequent 
cycles should be administered at that dose level, unless further dose reduction is required.  
Dose re-escalation is not allowed. Patients who cannot tolerate the lowest dose level will 
be discontinued from the study. 
 
 
 
Table 2. Dose Levels  
Dose Level 
Palbociclib 
Starting dose 
125 mg/d, 3 weeks on/1 week off 
-1 
100 mg/d, 3 weeks on/1 week off 
-2 
75 mg/d, 3 weeks on/1 week off 
-3 
75 mg/d, 5 days on 2 days off 
 
Discontinue Study Treatment 
 
Recommended dose modifications for treatment-related toxicities requiring treatment 
interruption/delay or persisting despite optimal medical treatment are described in Table 3.  
Table 3. Palbociclib Dose Modifications for Treatment Related Toxicities Requiring 
Treatment Interruption/Delay or Persisting Despite Optimal Medical Treatment. 
 
Toxicity 
Intervention with Palbociclib 
Uncomplicated Grade 3 
neutropenia 
(ANC ≥500 - <1000/mm3) 
 
 
 
• 1st occurrence: Hold drug. If ANC recovers (ANC > 1000) within 2 
weeks, resume at same dose.  
• If ANC takes longer than 2 weeks to recover (ANC>1000), but within 3 
weeks, then resume drug and decrease drug by 1 dose level. 
• Recurrent uncomplicated Grade 3: Hold drug.  If ANC recovers (ANC > 
1000) within 2 weeks, resume drug and decrease drug by 1 dose level. 
• For participants enrolled on Arm C, there is no action to palbociclib 
required for grade 3 uncomplicated neutropenia at Day 15 after cycle 2 
[cycle 3 and beyond]  
Grade 3 neutropenia 
(ANC<1000/mm3) 
associated with a 
documented infection 
or fever 38.5 
 
• Hold drug. If ANC recovers (ANC > 1000) within 2 weeks, resume drug 
and decrease drug by 1 dose level. 
• If ANC takes longer than 2 weeks to recover (ANC>1000), but within 3 
weeks, then resume drug and decrease drug by 2 dose levels. 
• If these parameters have not been met after 3 weeks of dose interruption 
(including the scheduled 1 week off treatment), the patient should 
permanently discontinue Palbociclib. 

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6.2 
Fulvestrant 
 
Discontinuation of fulvestrant for adverse events is very rare. However, in the unlikely 
event that the patient discontinues fulvestrant and is able to continue on palbociclib and/or 
avelumab, the investigator should contact the Medical Monitor to discuss the benefit-risk 
assessment of continuing with palbociclib and/or avelumab. 
 
There are no expected significant overlapping toxicities between fulvestrant and either 
palbociclib or avelumab. 
 
6.2.1 Fulvestrant Dose modifications/delays 
 
No dose reduction for fulvestrant is permitted. 
 
6.3 
Avelumab 
 
In the event that the participant holds or discontinues avelumab, therapy with other study 
medications may continue.   
Toxicity 
Intervention with Palbociclib 
Grade 4 neutropenia 
(ANC < 500/mm3) 
 
• First occurrence: Hold drug. Resume once ANC > 1000 and decrease 
dose by 1 dose level. 
• Recurrent Grade 4 neutropenia:  Hold drug. Resume once ANC > 1000 
and decrease dose by an additional dose level. 
Grade 3 or 4 
thrombocytopenia 
(platelet count < 75,000) 
• 1st occurrence: Hold drug until plt > 75,000, then resume drug and 
decrease by 1 dose level. 
• Recurrent Grade 3 thrombocytopenia: hold drug until plt >75,000, then 
decrease drug by an additional dose level. 
Grade 3 
non-hematologic toxicity 
(including, nausea, 
vomiting, diarrhea, 
and hypertension only if 
persisting despite 
optimal medical 
treatment); 
• 1st occurrence:  Hold drug until toxicity decreases to < Grade 1 or to 
baseline, then resume drug and decrease by 1dose level. 
• If toxicity takes longer than 2 weeks to recover to < Grade 1, but within 
3 weeks, then resume drug and decrease drug by 2 dose levels. 
• Recurrent toxicity: Hold drug until toxicity decreases to < Grade 1 or to 
baseline, then decrease drug by an additional dose level. 
Grade 2 non-hematologic 
toxicity persisting despite 
optimal medical treatment,  
deemed unacceptable in the 
investigator’s judgment, 
and lasting at least 2 
weeks; 
• 1st occurrence:  Hold drug until toxicity decreases to < Grade 1 or to 
baseline, then resume drug at same dose level. 
• Recurrent toxicity: Hold drug until toxicity decreases to < Grade 1 or to 
baseline, then resume drug and decrease by 1 dose level. 
LFTs 
Concurrent > 3XULN 
SGPT/ALT and 2X ULN 
total bilirubin 
 
Discontinue Palbociclib permanently. 

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6.3.1 Management of Immune-Related Adverse Events (irAEs) 
 
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment of 
irAEs is dependent upon severity (NCI-CTCAE grade) and in general consist of: 
• Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring 
• Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4: treat with high dose corticosteroids 
 
Please see Section 6.3.4 for more information about dose modifications and toxicity 
management with avelumab. 
 
6.3.2 Management of Severe Hypersensitivity or Flu-like Reactions Related to Avelumab 
In order to mitigate infusion-related reactions, premedication with an 
antihistamine and with acetaminophen is mandatory prior to the first 4 infusions of 
avelumab. Management of infusion-related reactions should follow guidelines set 
forth in Table 4. 
 
Table 4: Treatment Modification for Symptoms of Infusion-Related Reactions Caused 
by Avelumab 
NCI-CTCAE Grade 
Treatment Modification for Avelumab 
Grade 1 – mild 
• Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
• Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening 
 
Grade 2 – moderate 
• Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, Iv 
fluids); prophylactic medications indicated for  24 
h 
• Temporarily discontinue avelumab infusion 
• Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening 
Grade 3 or Grade 4 – severe or life-threatening 
• Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization 
indicated for clinical sequelae 
• Grade 4: Life-threatening consequences; urgent 
intervention indicated 
• Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject 
• Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment 
 
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for the next scheduled infusion.  If no 
infusion reaction is observed in the next scheduled infusion, the infusion rate may be 
returned to baseline at the subsequent infusions based on investigator’s medical 
judgment. If a subject experiences a Grade 3 or 4 infusion-related reaction at any time, 

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the subject must discontinue avelumab.  
 
6.3.3 Severe Hypersensitivity Reactions  
 
If hypersensitivity reaction occurs, the subject must be treated according to the best 
available medical practice. Subjects should be instructed to report any delayed reactions 
to the investigator immediately. 
 
Symptoms 
• Impaired airway 
• Decreased oxygen saturation (< 92%) 
• Confusion 
• Lethargy 
• Hypotension 
• Pale/clammy skin 
• Cyanosis 
 
Management 
• Epinephrine injection and dexamethasone infusion 
• Subject should be placed on monitor immediately 
• Alert intensive care unit for possible transfer if required 
 
 
6.3.4 Avelumab Dose modification/delays 
 
Treatment of immune related Adverse Events ( irAEs) should follow guidelines set forth in 
the following Table (per Investigator’s Brochure): 
 
 
 
 
 
Table 5. Management of Immune-related Adverse Events 
Gastrointestinal irAEs 
Severity of Diarrhea / Colitis 
(NCI-CTCAE v4.03) 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day over 
Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (for 
example, loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report 
worsening immediately 
If worsens: 
Treat as Grade 2 or 3/4  

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Grade 2 
Diarrhea:  4 to 6 stools per day 
over Baseline; IV fluids 
indicated < 24 hours; not 
interfering with ADL 
Colitis:  abdominal pain; blood 
in stool  
Hold avelumab therapy 
Symptomatic treatment 
If improves to Grade 1:  
Resume avelumab therapy 
 
If persists > 5 to 7 days or recur: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 stools 
per day over Baseline; 
incontinence; IV fluids ≥ 24 
hrs.; interfering with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs 
Grade 4:  life-threatening, 
perforation 
Hold avelumab for Grade 3.  
Permanently discontinue 
avelumab for grade 4 or recurrent 
grade 3. 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consider lower endoscopy  
If improves:  
Continue steroids until < Grade 1, 
then taper over at least 1 month, 
resume avelumab therapy 
following steroids taper for initial 
Grade 3 
If worsens or persists > 3 to 5 days, 
or recurs after improvement: 
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of 
perforation or sepsis  
Dermatological irAEs 
Grade of Rash 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body surface 
area  
Continue avelumab therapy  
Symptomatic therapy (for 
example, antihistamines, topical 
steroids)  
 
If persists > 1 to 2 weeks or recurs:  
Withhold Avelumab therapy  
Consider skin biopsy  
 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, taper 
steroids over at least 1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume avelumab therapy 
following steroids taper 
 
If worsens:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Grade 3: Covering > 30% body 
surface area;  
Grade 4: life threatening 
consequences  
Hold Avelumab for grade 3 
Permanently discontinue 
avelumab  for grade 4 or recurrent 
grade 3 
Consider skin biopsy  
Dermatology consult  
If improves to Grade < 1:  
Taper steroids over at least 1 
month; resume Avelumab therapy 
following steroids taper (for initial 
grade 3 

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1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent  
Add prophylactic antibiotics for 
opportunistic infections 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new 
laboratory cardiac biomarker 
elevations (e.g. troponin, CK-
MB, BNP) or cardiac imaging 
abnormalities suggestive of 
myocarditis.  
hold avelumab therapy 
Hospitalize. 
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management.     
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis.  
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If symptoms improve and immune-
mediated etiology is ruled out, re-
start avelumab therapy. 
 
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-mediated 
etiology is suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis. 
Immune-mediated myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate per 
cardiology consult.* 
Methylprednisolone 1-2 
mg/kg/day or equivalent.  
Add prophylactic antibiotics for 
opportunistic infections  
Once improving, taper steroids 
over at least 1 month 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A) 
*Local guidelines, or eg. AHA guidelines 

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Pulmonary irAEs 
Grade of Pneumonitis 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Radiographic changes only  
Consider holding avelumab 
therapy  
Monitor for symptoms every 2 to 
3 days  
Consider Pulmonary and 
Infectious Disease consults  
Re-image at least every 3 weeks 
If worsens:  
Treat as Grade 2 or Grade 3 to 4  
Grade 2 
Mild to moderate new 
symptoms  
Delay avelumab therapy 
Pulmonary and Infectious Disease 
consults 
Monitor symptoms daily, consider 
hospitalization  
1.0 to 2.0 mg/kg/day methyl-
prednisolone IV or oral equivalent  
Add prophylactic antibiotics for 
opportunistic infections.  
 
Consider bronchoscopy, lung 
biopsy  
Re-image every 1 to 3 days  
If improves:  
When symptoms return to < Grade 
1, taper steroids over at least 1 
month and then resume avelumab 
therapy following taper 
 
If not improving after 2 weeks or 
worsening:  
Treat as Grade 3 to 4  
Grade 3 to 4 
Grade 3: Severe new 
symptoms; New / worsening 
hypoxia;  
Grade 4: life-threatening  
Permanently discontinue 
avelumab therapy 
Hospitalize  
Pulmonary and Infectious Disease 
consults 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent  
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to < Grade 1:  
Taper steroids over at least1 month 
If not improving after 48 hours or 
worsening:  
Add additional 
immunosuppression (for example, 
infliximab, cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test 
Elevation 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Continue avelumab therapy 
Continue liver function monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4  

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Grade 1 AST or ALT > ULN 
to 3.0 x ULN and / or total 
bilirubin > ULN to 1.5 x ULN  
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and / or total bilirubin > 
1.5 to ≤ 3 x ULN  
Hold avelumab therapy 
Increase frequency of monitoring 
to every 3 days  
If returns to < Grade 1:  
Resume routine monitoring, 
resume avelumab therapy 
If elevations persist > 5 to 7 days 
or worsen:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN and / 
or total bilirubin > 3 x ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of monitoring 
to every 1 to 2 days  
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
Add prophylactic antibiotics for 
opportunistic infections  
Consult 
gastroenterologist/hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy if 
clinically warranted  
If returns to Grade < Grade 1:  
Taper steroids over at least 1 
month  
If does not improve in > 3 to 5 
days, worsens or rebounds:  
Add mycophenolate mofetil 1 
gram (g) twice daily  
If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines  
Renal irAEs 
Grade of Creatinine Increase 
(NCI-CTCAE v4) 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > ULN to 
1.5 x ULN 
Continue avelumab therapy 
Continue renal function monitoring 
If worsens: 
Treat as Grade 2 to 3 or 4. 
Grade 2 to 3 
Creatinine increased > 1.5 and 
≤ 6 x ULN 
Hold avelumab therapy 
Increase frequency of monitoring 
to every 3 days 1.0 to 2.0 
mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month, and resume avelumab 
therapy following steroids taper. 
If worsens: 
Treat as Grade 4. 
Grade 4 
Creatinine increased > 6 x 
ULN 
Permanently discontinue 
avelumab therapy 
Monitor creatinine daily 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent. 
If returns to Grade ≤1: 
Taper steroids over at least 1 
month. 

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Add prophylactic antibiotics for 
opportunistic infections 
Consider renal biopsy 
Nephrology consult 
Endocrine irAEs 
Endocrine Disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Continue avelumab therapy 
Endocrinology consult if needed 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)  
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as 
appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus) 
Hold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start thyroid hormone 
replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or 
insulin (for type I diabetes 
mellitus) as appropriate. 
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)  
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤ 1 (with or without hormone 
replacement/suppression). 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e. subnormal serum 
FT4 with 
Resume avelumab once symptoms 
and hormone tests improve to 
Grade ≤ 1 (with or without hormone 
replacement). 
In addition, for hypophysitis with 

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inappropriately low TSH and/or 
low serum cortisol with 
inappropriately low ACTH) 
Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women) 
Hormone 
replacement/suppressive therapy 
as appropriate 
Perform pituitary MRI and visual 
field examination as indicated 
 
If hypophysitis confirmed: 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month Hold 
avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed 
by corticosteroids taper during at 
least 1 month. 
Add prophylactic antibiotics for 
opportunistic infections. 
abnormal MRI, resume avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented. 
Continue hormone 
replacement/suppression therapy 
as appropriate. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.   
 
The study period, during which AEs and SAEs must be reported, begins after starting the first 
dose of study treatment and ends 30 days (90 days for Arm C) following the last administration 
of study treatment or study discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to study treatment. All AEs and SAEs 
whether volunteered by the subject, discovered by study personnel during questioning, or 
detected through physical examination, laboratory test, or other means will be assessed and 
reported, when appropriate. Abnormal laboratory values will not be reported unless deemed to be 
clinically significant based on the criteria listed in section 7.7. Each reported AE or SAE will be 
described by its CTCAE Version 4.0 term, grade, duration (i.e., start and end dates), regulatory 

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seriousness criteria if applicable, suspected relationship to Fulvestrant, Palbociclib or Avelumab, 
expectedness, and actions taken.  
 
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 Event List(s) for Palbociclib 
 
The primary anticipated toxicity of palbociclib is neutropenia.  In the phase I, dose-
escalation trial of palbociclib alone in advanced cancers42, neutropenia was the only dose-
limiting toxicity (DLT).  Grade 3 neutropenia during cycle 1 was observed in 3/22 patients 
receiving palbociclib 125 mg PO daily, with no grade 4 neutropenic events observed.  
Based on this result, 125 mg PO daily became the recommended phase 2 dose (RP2D).  
Other hematologic AEs of grade 3 or greater during cycle 1 were anemia and leukopenia, 
occurring in 1 and 4 of 41 patients, respectively.  The most common non-hematologic AEs 
of grade 3 or greater during cycle 1 were fatigue, nausea, and abdominal pain (each 
occurring in 2 of 41 patients).  Of note, there were no complicated hematologic AEs 
documented, and all hematologic AEs resolved during the off-drug period of a 3 week on/1 
week off schedule and were non-cumulative. 
 
In a phase II trial of palbociclib alone for advanced breast cancer, the only toxicities > 
grade 3 observed were transient neutropenia (50%) and thrombocytopenia (21%).30  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.31,32 The median time to first treatment delay for neutropenia was 58 days, and the 
median duration of treatment delay until recovery was 5 days (range 1-16 days). (Pfizer 
internal data). In general, hematologic abnormalities were adequately managed with 
standard supportive care, were not complicated, and resolved during the drug hold with no 
cumulative toxicity noted. 
In the phase I, dose-escalation trial of palbociclib alone in advanced cancers,42 QT interval 
changes were also evaluated in detail.  While 26 of 41 patients had a maximum increase of 
<30 msec from baseline QTc, zero patients had an on-treatment value exceeding 500 msec. 
 
The following toxicities have been observed with some frequency in patients given 
palbociclib: 
neutropenia, 
leukopenia, 
infections, 
fatigue, 
low 
hemoglobin, 
thrombocytopenia, inflammation of the mouth, diarrhea, constipation, nausea, vomiting, 
joint pain, back pain, pain in hands and feet, hair loss, rash, cough, dyspnea, headache, 
dizziness, anorexia, hot flush, insomnia, abdominal pain, indigestion, dry mouth, fever, 
asthenia, swelling of the hands and feet, irritation or sores in the lining of hollow organs 
like mouth, throat, stomach, bowels; pain, flu-like illness, muscle pain, pain in the muscles 
and bone including around the chest, muscle cramps, increases in blood liver markers that 
may indicate liver damage, dry skin, itching, mouth/throat pain, nosebleed, impaired sense 
of taste, high blood pressure, depression, fall, febrile neutropenia, lymphocytopenia, 

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blurred vision increased tearing and dry eye.  
 
Palbociclib is considered to have the potential to impair reproductive function and 
fertility in male humans based on nonclinical findings in rats and dogs. In a male rat 
fertility study, there were no effects on mating or fertility, but palbociclib-related findings 
in the testis and epididymis were consistent with repeat-dose toxicity findings, and 
correlated with lower sperm motility and density. Men should consider sperm 
preservation prior to beginning therapy with palbociclib. 
 
7.1.2 Adverse Event List(s) for Fulvestrant 
 
Fulvestrant is an ER antagonist indicated for the treatment of HR+ MBC in postmenopausal 
women with disease progression following anti-estrogen therapy. 
 
In a study with postmenopausal women with advanced breast cancer who had disease 
recurrence on or after adjuvant endocrine therapy or progression following endocrine 
therapy for advanced disease, the most frequently reported adverse events were injection-
site pain (11.6% of patients), nausea (9.7%), and bone pain (9.4%). Because fulvestrant is 
administered intramuscularly, it should be used with caution in patients with bleeding 
diatheses, thrombocytopenia, or anticoagulant use. For details regarding the safety profile 
of fulvestrant, refer to the fulvestrant package insert or SmPC. 
 
7.1.3 Adverse Event List(s) for Avelumab 
 
For the purpose of regulatory reporting requirements during clinical development, the 
following AEs will be considered as expected and met the threshold of causal association 
(based on comprehensive medical evaluation considering the mechanism of action and 
temporal relationship after excluding other possible etiologies) defined by the Sponsor. 
 
The following side effects have been observed among 1738 patients treated with 
avelumab according to the results from studies EMR100070-001 in various solid tumors 
(N=1650) and EMR100070-003 Part A in Merkel cell carcinoma (N=88) where 
avelumab was administered intravenously (IV) as single agent at a dose of 10 mg/kg 
every 2 weeks (Q2W)  
 
Three types of risks are associated with avelumab: general signs and symptoms, reactions 
that occur during or following the infusion, and immune-mediated side effects: 
• General signs and symptoms including fatigue, nausea, diarrhea, constipation, 
anorexia, weight loss, vomiting, anemia, abdominal pain, cough, shortness of 
breath, edema of the feet and legs, back pain, joint pain 
• Infusion related symptoms including hypersensitivity reactions which may 
include chills, shaking, fever, back pain, belly pain, shortness of breath or 
wheezing, decrease in blood pressure or hives.  
• Immune-mediated adverse reactions including immune-mediated colitis, 
pneumonitis, immune-mediated thyroid disorders including hyperthyroidism, 
hypothyroidism, thyroiditis and autoimmune thyroiditis; immune-mediated skin 

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reactions including rash, pruritis, redness, blisters, pemphigoid or peeling; other 
immune-mediated reactions including myocarditis, hepatitis, pneumonitis, 
pancreatitis, adrenal insufficiency, diabetes, uveitis, myosistis, Guillain-Barre 
syndrome  
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Expectedness: 
• Expected adverse events are those adverse events that are listed or characterized in the 
current adverse event list, the Package Insert, the Investigator Brochure or is included in the 
informed consent document as a potential risk. 
 
• Unexpected adverse events are those not listed in the Package Insert (P.I.) or current 
Investigator Brochure (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, 
under this definition, hepatic necrosis would be unexpected. 
 
 
7.3 
Serious Adverse Event Reporting  
 
7.3.1 In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the Overall PI. 
 
7.3.2 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 

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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.  
 
7.3.3 For Multi-Center Trials where a DF/HCC investigator is serving as the Sponsor, each 
participating institution must abide by the reporting requirements set by the DF/HCC. 
This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, unexpected grade 4 toxicities, and grade 5 
(death) regardless of study phase or attribution. 
 
7.4 
DF/HCC Adverse Event Expedited Reporting Guidelines 
 
The following adverse events must be reported to the DFCI IRB according to the expedited 
reporting guidelines: 
• CTCAE Grade 2 and Grade 3 Events – that are Unexpected and there is a Reasonable 
Possibility that the Adverse Event is related to the study Intervention. 
• CTCAE Grade 4 Events – Report all events that are Unexpected. Events that are 
Expected and listed within the protocol and/or current consent form do not need to be 
reported to the DFCI IRB. Please note, an event that presents at a higher severity than 
what is currently listed within the protocol and/or current consent as expected would be 
considered unexpected and reportable.  
• ALL CTCAE Grade 5 Events. 
 
Investigative sites within DF/HCC will report SAEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. For all events that meet the 
expedited reporting criteria, a full written adverse event report must be submitted to the DFCI 
IRB within 10 working days from notification of the event. 
 
Other investigative sites will report SAEs to their respective IRB according to their local IRB’s 
policies and procedures for reporting adverse events. A copy of the submitted institutional AE 
form will be forwarded to the Coordinating Center.  
 
The Coordinating Center will submit AE reports from outside institutions to the DFCI IRB 
according to DFCI IRB policies and procedures in reporting adverse events. 
 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.6 
Expedited Reporting to Pfizer  
 
Within 24 business hours of first awareness of the event (or immediately upon awareness if the 
event is fatal or life-threatening), the study team will report to Pfizer by facsimile any Serious 
Adverse Event (“SAE,” as defined below) for which reporting is required under this provision 

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(as described below).  Such SAEs are to be reported for study subjects or individuals otherwise 
exposed to the Pfizer Product (Palbociclib and/or Avelumab) as described below.  The study 
teams should report SAEs as soon as they are determined to meet the definition, even if complete 
information is not yet available. 
 
Study teams will report SAEs using Form FDA 3500A (MedWatch). The Reportable Event Fax 
Cover Sheet provided by Pfizer must also be included with each SAE submitted.   
   
7.6.1 SAE Definition for Reporting to Pfizer   
 
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 (i.e., substantial disruption of the ability to conduct normal life functions); or a 
congenital anomaly or birth defect.  Any other medical event that, in the medical judgment of 
the Principal Investigator, may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the outcomes listed above is also considered an SAE.  A 
planned medical or surgical procedure is not, in itself, an SAE.   
 
7.6.2 Exposure During Pregnancy, Exposure During Lactation, Occupational Exposure  
 
Even though there may not be an associated SAE, exposure to Palbociclib or Avelumab 
during pregnancy, exposure to Palbociclib or Avelumab during lactation, and occupational 
exposure to Palbociclib or Avelumab are reportable to Pfizer.   
 
7.6.3 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. 
  
7.6.4 Exclusions from SAE Reporting Requirements 
 
Specifically excluded from the reporting requirements for SAEs under this provision is any 
SAE identified in the protocol as anticipated to occur in the study population at some 
frequency independent of drug exposure, unless the Principal Investigator assesses such an 
event as related to study medication.  Also, specifically excluded from the reporting 
requirements is any SAE judged by the Overall Investigator to represent disease progression, 
unless it results in death within the SAE Reporting Period.   
 
7.6.5 SAE Reporting Period 
 
SAEs that are subject to reporting to Pfizer provisions are those that occur from after the first 
dose of study medication through 30 calendar days after the last administration of medication 

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in Arm B and at least  90 days of study medication in Arm C.  SAEs should be reported to 
Pfizer after the 30-day and/or 90-day period, respectively, if the Principal Investigator 
suspects a causal relationship between Palbociclib OR Avelumab and the SAE. SAEs 
occurring on Arm A are not reported to Pfizer.  
 
7.7 
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.  
 
7.8 
Routine Adverse Event Reporting 
 
All adverse events must be reported in routine study data submissions to the 
Overall PI on the toxicity case report forms. Grade 1 hematologic toxicity will not be reported on 
the case report forms unless they induce clinical signs or symptoms, require treatment or further 
diagnostic tests, or result in a dose hold or modification. All AEs on Cohort A and B must be 
followed until resolution or for 30 days after the subject’s last study visit, whichever comes first. 
Adverse events for patients on Cohort C will be followed until resolution or for at least 90 days 
after the subject’s last study visit, whichever comes first. 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 
 
 

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Chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-
ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one. 
Chemical formula: C24H29N7O2 
Molecular weight: 447.53. 
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 (IC50 = 11 nM; Ki = 2 nM) is metabolized to multiple metabolites in a qualitatively 
similar manner in rat, dog and human liver microsomes.  In vitro, Palbociclib is primarily 
metabolized by CYP3A4 and SULTA2A1 enzymes.  Information on potential drug interactions 
can be found in Section 6.4.   
 
8.1.2 Form 
 
Beginning in March-May 2020, Palbociclib will be supplied by Pfizer in a tablet formulation. 
There is no change to the active ingredient, dosage strengths or dosing schedule. The tablets 
will be packed in blister packs. The new packaging features basic calendarization and detailed 
patient instructions on how to take palbociclib throughout the treatment schedule.  
The new monthly box will contain 3 weekly blister packs of 7 tablets each along with the USPI for 
the tablet formulation. Each strength of tablet has a different shape or color as well as a different 
color carton similar to the way the current bottles have different colored labels (see below). 
 
 
Prior to the change to the tablet formulation, palbociclib is supplied by Pfizer as capsules 
containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib free base.  Pfizer will 
supply the oral drug formulation to sites in High Density Polyethylene (HDPE) bottles 
containing 75 mg, 100 mg, or 125 mg capsules.  The capsules can be differentiated by their 
size and color (see below). 
Table 6. 
Palbociclib capsule characteristics 
Dosage 
Capsule color 
Capsule size 
75 mg 
Sunset Yellow/Sunset Yellow 
2 

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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 or tablets should be stored at controlled room temperature (20-25C, 
59-86F) in their original container. 
Investigators and site staff are reminded to check temperatures daily (i.e. manually or by 
using alarm systems to alert of any excursions) and ensure that thermometers are working 
correctly as required for proper storage of investigational products.  These include 
thermometers for room storage.  Any temperature excursions must be reported to Pfizer.  
The investigational products must be stored as indicated.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.   
Once a deviation is identified, the investigational products (palbociclib) must be 
quarantined and not used until Pfizer provides documentation of permission to use the 
investigational product.  
Medication should be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Returned medication should be stored separately 
from medication that needs to be dispensed. 
 
8.1.4 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.  
 
8.1.5 Availability 
 
Palbociclib is an investigational agent and will be supplied free-of-charge from Pfizer 
using a commercial supply. 
 
8.1.6 Administration 
 
Beginning in March-May 2020, Palbociclib will be supplied by Pfizer in a tablet 
formulation. The tablets will be packed in blister packs containing either 75 mg, 100 mg 
or 125 mg tablets. Patients will be dispensed a monthly box containing 3 weekly blister 
packs of 7 tablets each along with the USPI for the tablet formulation.  
 The new smooth-coated tablet formulation offers patients the flexibility to take 
IBRANCE with or without food, 

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Palbociclib will be provided in non-patient-specific bottles containing either 75 mg, 
100 mg or 125 mg capsules.  
Site personnel must ensure that patients clearly understand the directions for 
self-medication.  Patients should be given a sufficient supply to last until their next study 
visit.  Unused drug and/or empty bottles should be returned to the site at the next study 
visit.  Unused returned medication MUST NOT be re-dispensed to patients. All empty 
bottles or unused medication returned by the patient will be destroyed on site after 
verification from the study team and the outpatient pharmacist.  
Palbociclib is an agent that must be handled and administered with care.  Patients should 
be instructed to keep their medication in the bottles provided and not transfer it to any 
other container.  Due to possible unknown hazards associated with topical and 
environmental exposure to experimental agents, capsules must not be opened and/or 
emptied into any vehicle for oral ingestion; capsules must be swallowed intact. 
Only a single capsule or tablet strength will be dispensed to the patient at each dispensing 
visit.  In the event of dose modification, request should be made of the patient to return 
all previously dispensed medication to the clinic and new capsules or tablets will be 
dispensed. 
 
8.1.7 Ordering 
 
Qualified personnel at participating sites will order the drug directly from Pfizer.   
 
8.1.8 Accountability 
 
To ensure adequate records, palbociclib capsules/tablets will be accounted for as 
instructed by Pfizer.  Patients are requested to return previously dispensed containers as 
well as their completed drug diary to the clinic at each visit for accountability purposes 
even if they will not be issued with new medication at that visit.  
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.) 
 
8.1.9 Destruction and Return 
 
Sites will document and destroy unused investigational product per their local policies.   
The site primary investigator must ensure that the materials are destroyed in compliance 
with applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.  Destruction must be adequately documented. 
 

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8.2 
Fulvestrant 
 
8.2.1 Description 
 
Fulvestrant injection for intramuscular administration is an estrogen receptor antagonist. 
The chemical name is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-
1,3,5-(10)- triene-3,17 beta-diol. The molecular formula is C32H47F5O3S and its 
structural formula is: OH OH (CH2)9SO(CH2)3CF2CF3 Fulvestrant is a white powder 
with a molecular weight of 606.77. The solution for injection is a clear, colorless to 
yellow, viscous liquid. 
 
Fulvestrant is commercially available and considered standard-of-care for patients with 
hormone receptor positive, metastatic breast cancer. The dose, schedule, and mode of 
administration used in this trial are identical to the dose, schedule, and mode of 
administration approved for use for this indication by the U.S. FDA. 
 
Fulvestrant will be charged to the patient and/or insurance company as it is considered 
standard-of-care. 
 
8.2.2 Form 
 
Fulvestrant injection is commercially available as a sterile, single patient, prefilled 
syringe containing 250 mg at a concentration of 50 mg/mL. The solution is a clear, 
colorless to yellow, viscous liquid. In addition to the fulvestrant, each injection contains 
as inactive ingredients alcohol, USP, benzyl alcohol, NF, and benzyl benzoate, USP, as 
co-solvents and castor oil, USP, as a co-solvent and release rate modifier. 
 
8.2.3 Storage and Stability 
 
Syringes of fulvestrant should be stored in the original container and refrigerated at 2-
8°C. 
 
8.2.4 Handling 
 
Fulvestrant requires no specific handling precautions. 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.  
 
8.2.5 Preparation 
 
Remove syringe from tray and check that it is not damaged. Peel open the safety needle 
outer packaging. Break the seal of the white plastic cover on the syringe luer connector to 
remove the cover with the attached rubber tip cap. Twist to lock the needle to the luer 
lock connector. Remove needle sheath. Remove excess air from the syringe (a small 
bubble may remain). 

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8.2.6 Administration 
 
Fulvestrant will be administered at a dose of 500 mg (2 x 250 mg injections) IM on Cycle 
1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, and on Day 1 of each subsequent cycle. Cycle 
length = 28 days.  
 
Fulvestrant will be administered slowly into each buttock. Immediately upon withdrawal 
of syringe from patient activate needle protection device by pushing lever arm forward 
until needle tip is fully covered. Visually confirm that the needle arm has advanced and 
that the needle tip is fully covered. If unable to activate, discard immediately into an 
approved sharps container. 
 
Fulvestrant must be administered at the study site.  
 
8.2.7 Ordering 
 
Fulvestrant is commercially available and will be ordered by each prescribing provider 
for the duration for the study. 
 
8.2.8 Accountability 
 
Fulvestrant is commercially available and therefore accountability should be performed 
as standard policy in the investigational site. 
 
8.2.9 Destruction 
 
Fulvestrant is commercially available and therefore destruction should be performed as 
standard policy in the investigational site. 
 
8.3 
Avelumab 
 
8.3.1 Pharmaceutical Properties 
 
Avelumab drug product is a sterile, clear, and colorless concentrate for solution for infusion 
presented at the concentration of 20 mg/mL in European Pharmacopeia (Ph. Eur.) and 
United States Pharmacopeia (USP) type I glass vials closed with a rubber stopper and 
sealed with an aluminum Flip Offiaronmp crimp seal closure. 
 
8.3.2 Description of the Formulations 
 
Each single-use vial contains 200 mg of avelumab as a preservative-free acetate-buffered 
solution(pH 5.2) containing Mannitol, and Polysorbate 20 (Tween 20).  
 
8.3.3 Instructions for Storage 
 

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Avelumab drug product must be stored at 2°C to 8°C until use. The storage condition is 
based on data from ongoing long term stability studies with avelumab. Avelumab drug 
product stored at room (23°C to 27°C) or higher temperatures for extended periods of time 
might be subject to degradation. Avelumab drug product must not be frozen. Rough 
shaking of the solution must be avoided. For administration in clinical trials, avelumab 
drug product must be diluted with 0.9% saline solution (sodium chloride injection) supplied 
in an infusion bag. The immediate administration of the prepared solution for dosing kept 
at room temperature is preferred.  In case the aseptically prepared dosing solution cannot 
be administered immediately after preparation, the acceptable holding time is: not more 
than 24 hours under refrigerated conditions (2-8°C, 36-46°F) with no more than 8 of those 
hours at room temperature (15-25°C, 59-77°F), including infusion time. 
 
No other drugs should be added to the solution for infusion containing avelumab. 
 
8.3.4 Handling of the Dosage Forms 
 
For administration in clinical trials, avelumab drug product must be diluted with 0.9% 
saline solution (sodium chloride injection) supplied in an infusion bag. Detailed 
information on infusion bags and medical devices to be used for the preparation of the 
dilutions and subsequent administration will be provided in the IP Manual. 
 
To prepare the dilutions, subsequent preparation steps must be accomplished by adequate 
trained personnel under a laminar flow box using aseptic techniques: 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to 
room temperature for a minimum of 30 minutes. Use a disposable syringe equipped with 
a needle of suitable size to remove a volume of sodium chloride solution to be replaced 
by avelumab from the infusion bag and discard the removed solution. Use a new 
disposable syringe equipped with a needle of suitable size to inject a volume of avelumab 
drug product identical to the discarded volume of sodium chloride solution into the 
infusion bag. Gently invert the mixture 10 times. Infusion bags must not be shaken, in 
order to avoid foaming or excessive shearing of the protein solution. The preparation 
must be carefully inspected as it should result in a homogeneous looking clear solution, 
free of visible particles. 
 
8.3.5 Compatibility 
 
There are no known compatibility issues for co-administration of avelumab with any of 
the other agents. 
 
8.3.6 Availability 
Avelumab is an investigational agent and will be supplied free-of-charge from Pfizer. 
 
8.3.7 Preparation and Administration 
 
Only clinical site personnel who are appropriately trained on the procedures may perform 
the preparation and administration step specified in the IP Manual. Clinical site personnel 

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involved in these procedures must comply with all applicable regulations and standards. 
The preparation and administration of all sterile products must be performed using 
aseptic technique. Utilize local site procedures as appropriate. 
 
Avelumab) infusion solutions must be prepared in 0.9% Sodium Chloride (Normal 
Saline) and the final concentration of MSB0010718C (avelumab) in the infusion 
solutions must be between 0.016 mg/mL to 8 mg/mL. Total volume of final prepared 
solution must be 250 mL. Investigational drug products must be inspected visually for 
particulate matter and discoloration (i.e. change in color) prior to administration, 
whenever the solution and container permit. If particulates or discoloration are observed, 
do not use the vial(s) and notify the Principal Investigator or designee. Do not shake or 
freeze the vial(s). The final IP must be administered within 24 hours of preparation stored 
at room temperature 15 to 25 °C, 59 to 77 °F. Dose preparation must be performed using 
sterile handling techniques in compliance with local, state, and national laws/regulations. 
Avelumab MUST be administered with a low protein binding 0.2 micron PES filter. Each 
vial is for single-use only. Each vial is for use in a single patient, for a single dose. 
Avelumab is administered over 1 hour (-10/+20 minutes).  
 
8.3.8 Ordering 
 
Qualified personnel at participating sites will order the drug directly from Pfizer.   
 
8.3.9 Accountability 
 
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 
 
All opened (i.e. aluminum overseal broken) vials (full, partially used, and empty) may be 
destroyed at the site by the appropriate site personnel local environmental requirements 
and institutional policies. Discarded volumes of IP solutions must be disposed of as 
pharmaceutical waste according to local site procedures. Destruction must be adequately 
documented.  
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Correlative Studies Background 
 
The following outline provides a brief overview of the correlative studies.  
 

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The application of whole-exome and/or RNA sequencing will be applied in an effort to 
characterize the molecular landscape of breast cancer and further discovery of novel predictors 
of extraordinary therapeutic response (including “mutational burden” as a potential predictor of 
response to PD1/PDL1 therapy for patients receiving avelumab). Additional exploratory studies 
not listed here may be pursued in the future if deemed relevant to the study goals. Additional 
details regarding the rationale behind these correlative objectives can be found in the 
introductory/background comments in Section 1. The circulating tumor cells will be analyzed by 
Northwestern University. All other correlative studies will be analyzed with collaboration by the 
Broad Institute other than the cfDNA sample that will be analyzed at Guardant Health. 
Additional details regarding specimen collection, storage, shipping, and processing can be found 
in the PACE Study Manual. 
 
• Archival Tissue: H+E staining; immunohistochemistry for ER, PR, HER2, Rb, pRB, pAKT, 
PD-L1; whole-exome sequencing (WES); RNA sequencing (RNAseq) 
 
• Pre-Treatment/Post-Treatment Biopsy (Optional): H+E; immunohistochemistry for ER, PR, 
HER2, Rb, pRB, pAKT, PDL1; WES; RNAseq 
 
• Whole Blood: germline DNA sequencing, HLA-typing 
 
• Cell-free DNA: WES; including, but not limited to, Rb, ESR1, PIK3CA 
 
• Circulating tumor cells: including, but not limited to, CTC enumeration and ER expression  
 
• Plasma: circulating markers of response and/or resistance to study therapy including, but not 
limited to cytokines and/or growth factors 
 
Variation in genetic markers and other biomarkers may help to explain some of the variability in 
response seen with some drugs among different individuals. This is referred to as 
pharmacogenomic/biomarker research. Comparing the DNA, RNA, protein, and metabolite 
variation patterns of patients who respond well and those who respond poorly to treatment may 
help to better define the most appropriate group of patients in which to target a given treatment. 
For example, the biospecimens may be used to evaluate whether certain patients are more likely 
to benefit from the addition of palbociclib to fulvestrant compared to fulvestrant alone.  
 
9.2 
Specimen Submission Requirements  
 
The following specimens are to be submitted to the indicated lab. Refer to the separate PACE  
Study Manual for additional processing and shipping instructions.  Sample collection kits will be 
provided to sites by Core Prognostex. Guardant Health will provide the sample collection and 
shipping materials for the Guardant cfDNA sample.  
 
Required Specimen Submissions 
Specimen Type 
Collection Time Point 
Shipping 
Condition 
Ship to 
Baseline  
C2 D1 
C3D1 
 
C5 D1 
 
 
Progression
/ EOS 

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Paraffin block (or 15 
unstained slides) a 
X 
 
 
 
 
Ambient 
temperature 
DFCI Smith 
Laboratory 
1 H&E stained slide 
X 
 
 
 
 
Ambient 
temperature 
DFCI Smith 
Laboratory 
Streck Tubes 
(circulating cfDNA) b 
X 
X 
X 
X 
X 
Ambient 
temperature 
DFCI Smith 
Laboratory 
Guardant Health 360 
cfDNA sample 
X 
 
 
X 
 
X 
Ambient 
temperature 
Guardant 
Health 360 
Plasma (EDTA tube) 
X 
 
 
 
X 
Frozen 
DFCI Smith 
Laboratory 
2 Lavender Top EDTA 
Tubes (germline 
DNA)c 
 
X 
 
 
 
Thermos 
provided by 
Core 
Prognostex  
DFCI Smith 
Laboratory 
CTC sample (2 10 mL 
CellSave tubes) 
X 
 
X 
 
X 
Ambient 
temperature 
Northwestern 
Lab 
Fresh and frozen tumor 
tissue  (optional 
biopsy)d 
X 
 
 
 
X 
Frozen in 
OCT & 
ambient in 
formalin 
DFCI Smith 
Laboratory 
a. 
Preference for metastatic sample if available. Archival tissue can be collected at any time point throughout 
the study. 
b. 2 Streck top tubes will be collected for cfDNA at baseline, time of each restaging, and progression or 
treatment discontinuation.  
c. 
Sample for germline mutation should be collected at C2D1 or at any time during treatment   
d. Baseline and Off-Treatment research biopsies are optional, but strongly encouraged, for patients with “easily 
accessible disease” and “accessible disease”.   
 
9.3 
Translational Research Blood  
 
 
Streck Tube (blood sample for cell-free DNA)  
Blood will be collected for ctDNA analysis via 2 10 mL Streck tubes prior to dosing at Cycle 1 
Day 1, Cycle 2 Day 1, at every restaging, and at time of disease progression or study 
discontinuation visit, whichever comes first. Collection tubes for research blood samples will be 
in the research sample collection kit provided by Core Prognostex. Instructions for collection, 
labeling, and shipment are included within the PACE Study Manual.  
 
Guardant Health cfDNA 
An additional single 10 mL Streck tube will be collected at baseline, C3D1, and off-treatment for 
Guardant Health 360. This sample kit will be provided by Guardant Health and the instructions 
for collection, labeling, and shipment are included within the Guardant Lab Manual.  
 
 
DO NOT FREEZE OR REFRIGERATE STRECK TUBES.  
 
Plasma Sample 
Blood will be collected for plasma via a 10 mL EDTA tube (lavender top) at baseline and at time 
of progression or study discontinuation visit, whichever comes first. Instructions for collection, 

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labeling, and shipment are included within the PACE Study Manual. 
 
Germline DNA Blood Collection  
Two 10 mL Lavender top [EDTA] tubes of whole blood will be collected at Cycle 2 Day 1 for 
extraction of germline DNA. If it is missed, the sample may be drawn at any time during 
treatment. Collection tubes for research blood samples will be in the research sample collection 
kit provided by Core Prognostex. Instructions for collection, labeling, and shipment are included 
within the PACE Study Manual.  
 
DO NOT REFRIGERATE/FREEZE OR CENTRIFUGE.  
 
CTC Collection 
Two 10 mL CellSave tubes will be collected at baseline, at time of first restaging (C3D1), and 
off-treatment for CTC analysis. Collection tubes for research blood samples will be in the 
research sample collection kit provided by Core Prognostex. Instructions for collection, labeling, 
and shipment are included within the PACE Study Manual.  
 
DO NOT REFRIGERATE/FREEZE OR CENTRIFUGE.  
 
9.4 
Tumor Biopsies 
 
Optional Tumor Biopsy will be performed at the following time-points: 
• Baseline (Pre-Treatment): to be performed up to 2 weeks prior to starting treatment. 
Optional for patients with accessible disease or easily accessible disease.  
• Off-Study/Disease Progression: to be performed after disease progression has been 
determined prior to initiation of subsequent therapy. Optional for patients with easily 
accessible and accessible disease 
 
Fresh and frozen tumor samples from research biopsy will be shipped with the Specimen 
Requisition form found in the PACE Study Manual.  Instructions for collection, labeling, and 
shipment are included within Appendix E and the PACE Study Manual.  
 
 
9.5 
Archival Tissue Collection 
 
The following archival tissue specimens are required for gene profiling:  
• 1 paraffin block (or 20 unstained slides 4-5μm thick)  
• 1 H&E slide  
 
Archival tissue will be collected for all participants. Preference is for tissue from metastatic 
biopsy or surgery rather than primary breast cancer diagnosis. Archival tissue sample is shipped 
ambient in conventional paraffin block or slide shipper to the DFCI PACE study team with the 
Specimen Requisition form found in the PACE Study Manual. The PACE Study Manual 
contains additional information on labeling and shipment of archival tissue to DFCI. Paraffin 
blocks will be returned after completion of correlative research. Unstained slides will not be 
returned.  

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10. STUDY CALENDAR 
 
All subjects must sign an informed consent document prior to initiation of any study related 
procedures. The consenting individual for the clinical trial must be an MD listed as a co-
investigator on the trial. 
 
Baseline evaluations are to be conducted < 14 days prior to start of protocol therapy. Scans must 
be done <4 weeks (+7 days) prior to the start of therapy.  If performed at baseline < 7 days of 
C1D1, procedures do not need to be repeated to initiate treatment.   
 
All assessments must be performed prior to administration of any study medication. Day 15 study 
assessments must be performed within  +/- 3 days of the protocol-specified date, unless otherwise 
noted. Day 1 study assessments for Cycle 2 and beyond must be performed within +/- 3 days of 
the protocol-specified date.  Day 14 Avelumab dose must be administered within +/- 2 days. 
Restaging CT or MRI scans and bone scans may be done +/- 7 days of the protocol-specified date, 
though it is preferred that they occur within the +/- 3 day window if possible.  
 
Cycle 2 Day 15 laboratory assessments may be performed locally if appropriate plan is in place 
for the study site to receive and review results in a timely manner.  
 
If treatment is held, the calendar of assessments should remain on schedule. Restaging scans 
should not be delayed. 
 
After time of progression, patients will be followed for survival at least every 6 months until time 
of death.  If a patient is taken off protocol treatment for any reason other than progression or death, 
then the patient should also be followed for progression with staging scans no less than every 12 
weeks until disease progression, start of alternative anti- cancer therapy, death, or withdrawal of 
consent, whichever comes first. These patients should also be followed for survival every 6 months 
until time of death.  
 

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Table 7. Study Calendar 
 
Pre-Study 
Cycle 1 
Cycle 2 
Subsequent Cycles 
Follow-up 
 
< 14 days of 
registration 
D1 
D15 
D1 
D15 
C3 
D1 
D1 of each 
cycle 
At time of progression 
or off treatment 
Safety Follow-upi 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
+ 3 days 
Physical exam, ECOG PS 
X 
X f 
 
X 
 
X 
X 
X 
 
Vital signs, weight 
X 
X f 
 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
CBC w/diff a 
X 
X f 
X 
X 
X 
X 
X 
X 
 
Serum chemistry a 
X 
X f 
X 
X 
X 
X 
X 
X 
 
Free T4, TSH, ACTH 
X 
 
 
X 
 
 
Xg 
 
 
HBV sAg , HCV Ab   
X 
 
 
 
 
 
 
 
 
12-lead EKG  
X 
 
 
 
 
 
 
 
 
B-HCG b 
X 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
 
X 
 
X 
X 
 
 
AE evaluation 
X 
 
 
X 
 
X 
Xh 
X 
 
Tumor measurements c 
X 
 
 
 
 
X 
X 
 
 
Bone scan d 
X 
 
 
 
 
 
 
 
 
Research blood, biopsy, or 
tissue e 
X 
X 
 
X 
 
X 
Every 2 
cycles 
X 
 
Survival/safety follow-up 
 
 
 
 
 
 
 
X 
X 
 
a. 
Serum chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose (random), total bilirubin, alkaline phosphatase, 
ALT, AST, albumin, calcium, magnesium, phosphorus, and CK [CK required for Arm C only]. CBC and chemistries are required prior to each 
Avelumab dose in Arm C. C2 Day 15 laboratory assessments are not required for Arm A.   
b. In women of childbearing potential only (including premenopausal women with intact uterus and ovaries on GnRH agonist).  
c. 
Baseline tumor assessments <4 (+7 days) weeks prior to the start of therapy. Subsequent assessments every 8 weeks (2 cycles, +/- 7 days) until 24 
weeks at which point the interval may be extended to every 12 weeks, (3 cycles +/- 7 days). See Section 11.  

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d. Baseline whole body bone scan <4 (+7 days) weeks prior to the start of therapy. For patients with measurable disease, skeletal lesions identified on the 
whole body bone scan at baseline, which are not visible on the chest, abdomen and pelvis CT (or MRI) scan should be imaged at baseline and followed 
using localized CT, MRI or x-ray. Whole body bone scans need not be repeated after baseline unless clinically indicated. For patients with bone only 
disease, whole body scans will be performed every 6 months to confirm response, or earlier if clinically indicated.  
e. 
See Section 9. 
f. 
If performed at baseline < 7 days of C1D1, procedures do not need to be repeated to initiate 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. 
g. After Cycle 4, endocrine tests are required every 2 cycles 
h. Adverse events must be evaluated prior to every Avelumab infusion for patients on Arm C prior to infusion.  
i. 
Adverse events will be collected until 30 days (Arms A and B) or at least 90 days (Arm C) after last dose of study treatment. AE collection after 
participants have come off treatment can occur within a +2-week window of the defined period. Patients will be followed for long term survival every 6 
months or until death either via a site visit or via a telephone call. See Section 5.7.

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11. MEASUREMENT OF EFFECT 
 
For the purposes of this study, participants should be evaluated within 4 weeks of treatment start 
and re-evaluated for response every 8 weeks (2 cycles). After 24 weeks (cycle 6), tumor 
measurements can be performed every 12 weeks (3 cycles). 
 
Confirmation of CR or PR are not required for best overall response determination in this trial. 
All primary and secondary endpoints based on radiological assessments of tumor burden will be 
derived using the local radiologist’s/investigator’s assessment.  
 
Contrast computed tomography (CT) (or without contrast if contraindicated) of chest and 
abdomen is preferred. Magnetic resonance imaging (MRI) of chest and abdomen is an acceptable 
alternative. Note: PET-CT scans are not allowed per protocol for primary assessment of 
response. PET-CT scans may be done according to clinical judgment to supplement CT or MRI 
scans in cases where results of the PET-CT may clarify or resolve a clinical question. If 
palpable/visible lesions (e.g. chest wall nodule, etc) is being used as a target lesions, 
measurements and photographs should be taken as well. 
 
 
11.1 
RC: RECIST Criteria 
 
Response and progression will be primarily evaluated in this study using the 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.  
Bone only disease, if there are lytic lesions, is also allowed and treatment response will be 
evaluated based on the MD Anderson criteria. (Note:  Participants who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
Evaluable for PFS. All participants randomized on this study are considered to be evaluable 
for PFS    (whether or not they are eligible, have measurable disease, or receive protocol 
therapy). 

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11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest 
x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
   A lesion in a previously irradiated area is not eligible for measurable disease unless there 
is objective evidence of progression of the lesion prior to study enrollment. Lesions in 
previously irradiated areas must be clearly identified as such. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-
measurable. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered target lesions if the soft tissue component meets the definition of measurability 
as defined above. These lesions will be evaluated by the RECIST 1.1 criteria. Lytic bone 
lesions or mixed lytic-blastic lesions that can be evaluated by cross sectional imaging 
techniques such as CT or MRI can be considered target lesions and response will be 
evaluated using the MD Anderson (MDA criteria) [41]. ‘Cystic lesions’ thought to 
represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in 
the same participant, these are preferred for selection as target lesions. Lesions in 
previously irradiated areas or areas subject to other loco-regional therapy are usually not 
considered measurable unless there has been demonstrated progression of that lesion. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 

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in addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, 
or digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 2 weeks before the beginning 
of the treatment. 
 
Measurements are based on the sum of a perpendicular, bidimensional measurement of the 
greatest diameters of each individual lesion. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the anti-tumor effect of a treatment. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or 
less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 

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be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
Ultrasound (US). When the primary endpoint of the study is objective response evaluation, 
US should not be used to measure tumor lesions. It is, however, a possible alternative to 
clinical measurements of superficial palpable lymph nodes, subcutaneous lesions, and 
thyroid nodules. US might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 
 
FDG PET and PET/CT. The acquisition of FDG PET and FDG PET/CT scans should 
follow the NCI Guidelines for using FDG PET as an indicator of therapeutic response (L.K. 
Shankar et al, Consensus recommendations for the use of 18F- FDG PET as an indicator 
of therapeutic response in patients in National Cancer Institute Trials. J Nucl Med, 
47(6):901-903, 2006). Patients should avoid strenuous exercise and be on a low 
carbohydrate diet for 24 hours prior to the scan. Patients should fast for 4 hours or longer 
prior to the FDG injection and should have a serum glucose of less than 200 mg/dL at the 
time of FDG injection. A 10-20 mCi dose of FDG should be injected for typical adult 
patients. For longitudinal studies with multiple scans, particular attention should be paid to 
ensure consistent patient preparation and acquisition parameters between the follow-up 
scan and the baseline scan. When designing a study where PET scans are going to be 
utilized as one of the modalities to evaluate efficacy, it is important to consult with 
physicians in nuclear medicine in designing the appropriate criteria to be utilized. In this 
protocol, PET or PET/CT should NOT be used as the primary modality to evaluate 
objective response, but may be used in an adjunctive fashion together with either CT or 
MRI in cases of uncertainty, as clinically indicated. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific context 
require sophisticated equipment and a high level of expertise that may only be available in 
some centers. Therefore, the utilization of such techniques for objective tumor response 
should be restricted to validation purposes in reference centers. However, such techniques 
may be useful to confirm complete pathological response when biopsies are obtained. In 
this protocol, endoscopy or laparoscopy will not be used for evaluation of response. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a subject to be considered 
in complete clinical response. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 

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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. 
 
11.1.4 Response Criteria  
 
a. 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. 
 
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.   
 
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. 
 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
 
b. Evaluation of Lytic Bone Lesion Target Lesion (MDA criteria)  
 
Response 
category 
Criteria 
Complete response 
Complete sclerotic fill-in of lytic lesions on x-ray or CT scan. 
 
Normalization of bone density on x-ray or CT scan. 
 
Normalization of signal intensity on MRI. 
 
Normalization of tracer uptake on skeletal scintigraphy 

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c. Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD):  Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. 
 
Partial Response  
Development of a sclerotic rim or partial sclerotic fill-in of lytic 
lesions on x-ray or CT scan. 
Osteoblastic flare - Interval visualization of lesions with 
sclerotic rims or new sclerotic lesions in the setting of other 
signs of PR and absence of progressive bony disease. 
≥ 50% decrease in measurable lesions on x-ray, CT, or MRI. 
≥ 50% subjective decrease in the size of ill-defined lesions on 
x-ray, CT, or MRI. 
≥ 50% subjective decrease in tracer uptake on skeletal 
scintigraphy. 
Progressive Response 
≥ 25% increase in size of measurable lesions on x-ray, CT, or 
MRI. 
≥ 25% subjective increase in the size of ill-defined lesions on 
x-ray, CT, or MRI. 
≥ 25% subjective increase in tracer uptake on skeletal scintigrap
New bone metastases. 
 
Stable Disease 
No change 
< 25% increase or < 50% decrease in size of measurable lesions 
< 25% subjective increase or < 50% subjective decrease in size 
of ill-defined lesions 
No new bone metastases 
 

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Progressive Disease (PD):  Appearance of one or more new lesions* (new lesions must be 
> slice thickness) and/or unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.     
 
Unknown (UN): Assessment of non-target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
 
Note: If tumor response data is missing for target lesions, the overall assessment must be 
Unknown (UN) unless there is new disease that would result in an overall assessment of 
PD. However, if there is missing or unevaluable data for non-target lesions, but data is 
available for all target lesions, the overall response for that time point will be assigned 
based on the sum LD of all target lesions. Additionally, the assessment of CR cannot be 
made if there is missing or unevaluable data for non-target lesions. In this case, the overall 
assessment would be PR. 
 
Overall level of substantial worsening that merits discontinuation of therapy. A useful test 
that can be applied when assessing non-targets for unequivocal progression is to consider 
if the increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease. 
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). 
 
d. Evaluation of New Lesions 
 
Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not due 
to difference in scanning technique, imaging modality, or findings thought to represent 
something other than tumor (ex: new bone lesions may be healing or flare of pre-existing 
lesions). However, a lesion identified on a follow-up scan in an anatomical location that 
was not scanned at baseline is considered new and will indicate PD. If a new lesion is 
equivocal (because of small size, etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be declared using the 
date of the initial scan on which the lesion was discovered. 
 
e. Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response 
assignment will depend on measurement criteria. 
 
Objective response will be defined as best overall response of CR or PR. Otherwise, the 
patient will be considered as non-responder; this includes patients with inadequate data for 
tumor assessment.  

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Clinical benefit will be defined as best overall response of CR or PR or stable disease of at 
least 24 weeks duration. Otherwise, the patient will be considered as non-responder; this 
includes patients with inadequate data for tumor assessment. 
 
 
Table 8. For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New Lesions* 
Overall Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
CR 
UN 
No 
PR 
PR 
SD or UN  
No 
PR 
SD 
SD or UN 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
Table 9. For Participants with Non-Measurable Disease  
Non-Measurable Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
PR 
No 
PR 
SD or UN 
No 
SD 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
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. 
 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started, or 

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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 recurrent or 
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 progressive disease is objectively documented, 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 to the earlier of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation. The Statistical 
Analysis Plan will document special cases of PFS definition and censoring criteria. 
 
11.2 
irRC: Immune-Related Response Criteria 
 
Definition of Tumor Response Using irRC 
 
NOTE: This section is for secondary endpoint assessment to be used only for patients in Arm C. 
 
RECIST 1.1 has its shortcomings for targeted immunotherapy in oncology, as RECIST may not 
accurately capture the ‘flare effect’ - pseudo-progression effect – which can be seen with 
immunotherapy agents, and may declare progressive disease too early, when the treatment effect 
is not yet fully evident. Immune related Response Criteria (irRC) were created to provide better 
assessment of the effect of immunotherapeutic agents. (Wolchok et al, CCR 2009)  
 
The sum of the products of the two largest diameters of lesions (SPD) at tumor assessment using 
the immune-related response criteria (irRC) for progressive disease incorporates the contribution 
of new measurable lesions. Each net Percentage Change in Tumor Burden per assessment using 
irRC criteria accounts for the size and growth kinetics of both old and new lesions as they appear. 
 
 
 
11.2.1 Definition of Target Lesions Response Using irRC 
 
• irComplete Response (irCR): Complete disappearance of all target lesions. This 
category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 
• irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum 
of the products of the two largest perpendicular diameters of all target and all new 

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measurable lesions (i.e., Percentage Change in Tumor Burden). Note: the appearance of 
new measurable lesions is factored into the overall tumor burden, but does not 
automatically qualify as progressive disease until the SPD increases by > 25% when 
compared to SPD at nadir. 
 
• irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease.  
 
• irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor 
Burden (i.e., taking SPD of all target lesions and any new lesions) when compared to 
SPD at nadir. 
 
11.2.2 Definition of Non-Target Lesions Response Using irRC 
 
• irComplete Response (irCR): Complete disappearance of all non-target lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 
• irPartial Response (irPR): Non-target lesion(s) are not considered in the definition of 
PR; this term does not apply. 
 
• irStable Disease (irSD): Does not meet the criteria for irCR or irPD. 
 
• irProgressive Disease (irPD): Increases in number or size of non-target lesion(s) does 
not constitute progressive disease unless/until the Percentage Change in Tumor Burden 
increases by 25% (i.e., the SPD at nadir of the target lesions increases by the required 
amount). 
 
11.2.3 Impact of New Lesions on irRC 
 
New lesions in and by themselves do not qualify as progressive disease. However their 
contribution to total tumor burden is included in the SPD which in turn feeds into the 
irRC criteria for tumor response. Therefore, new non-measurable lesions will not 
discontinue any subject from the study. 
 
11.2.4 Definition of Overall Response Using irRC 
 
Overall response using irRC will be based on these criteria: 
 
• Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (target and non-target together with no new measurable/unmeasurable lesions) for 
at least 4 weeks from the date of documentation of complete response. 
 
• Immune-Related Partial Response (irPR): The sum of the products of the two largest 
perpendicular diameters of all target lesions is measured and captured as the SPD 
baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular 
diameters of all target lesions and of new measurable lesions are added together to 

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provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to 
baseline of the irSPD compared to the previous SPD baseline, of 50% or greater is 
considered an immune Partial Response (irPR). 
 
• Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria 
for immune complete response or immune partial response, in the absence of progressive 
disease. 
 
• Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to 
confirm PD by serial imaging. Any of the following will constitute progressive disease: 
− At least 25% increase in the SPD of all target lesions over nadir SPD calculated for the 
target 
lesions. 
− At least a 25% increase in the SPD of all target lesions and new measurable lesions 
(irSPD) over the nadir SPD calculated for the target lesions. 
 
Table 10: Immune-Related Response Criteria Definitions 
Target 
Lesion 
Definition 
Non-Target 
Lesion 
Definition 
New 
Measurable 
Lesions 
New Non-
measurable lesions 
Percent change in tumor 
burden (including 
measurable new lesions 
when present) 
Overall irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100%  
irCR 
Partial 
Response 
Any 
Any 
Any 
> 50 % 
irPR 
< -50% to +25% 
irSD 
> +25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
< -50% to +25% 
irSD 
> +25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
> 25 % 
irPD 
 
11.2.5 Immune-Related Best Overall Response Using irRC (irBOR) 
 
irBOR is the best confirmed irRC overall response over the study as a whole, recorded 
between the date of first dose until the last tumor assessment before subsequent therapy 
(except for local palliative radiotherapy for painful bone lesions) for the individual 
subject in the study. For the assessment of irBOR, all available assessments per subject 
are considered. 
 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a 
second (confirmatory) evaluation meeting the criteria for response and performed no less 
than 4 weeks after the criteria for response are first met. 
 
11.2.6 Confirmation of Progressive Disease in Arm C Avelumab Arm 
  
Avelumab, like other immunotherapeutic agents, may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen 

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with such an approach may extend beyond the typical time course of image responses 
seen with cytotoxic agents, and can manifest as a clinical response after an initial increase 
in tumor burden or even the appearance of new lesions. 
  
For any subject in Arm C who showed first radiologic evidence of progressive disease 
(PD) by RECIST 1.1 and is deemed clinically stable, it is at the discretion of the 
investigator to continue treating the subject until progression is confirmed at least 4 
weeks from the date of the first radiologic evidence of PD. If progression is confirmed, 
the subject will be discontinued from study treatment. Otherwise, the subject will 
continue treatment and radiographic scans. Any subject who had initial radiologic 
progression and is deemed clinically unstable should be discontinued from both study 
drugs and no subsequent scan for confirmation is required. 
  
Further details are as below: 
  
For purposes of PFS assessment on this trial, in addition to radiographic assessment of 
tumor 
response or progression, the investigator should into account the clinical 
condition/stability of subjects. 
  
Clinically stable is defined by the following criteria: 
 
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor(s) at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
  
Any subject who showed first radiologic evidence of progressive disease and is deemed 
clinically unstable should be discontinued from study drugs and is not required to have 
repeat imaging for confirmation. 
  
For a clinically stable subject with first radiologic evidence of progressive disease (ie, 
unconfirmed progression of disease), it is at the discretion of the investigator to continue 
treating the subject with the assigned treatment per protocol until progression of disease 
is confirmed on a subsequent scan at least 4 weeks later. If progression is not confirmed 
on the subsequent scan, the subject should continue to receive study treatment and have 
radiographic scans performed every 8 weeks if the patient has been on study for less than 
24 weeks, or every 12 weeks for patients who have been on study greater than 24 weeks 
to monitor disease status. If radiologic progression is confirmed by subsequent scans, 
then the subject will be discontinued from study treatment. Exceptions may be considered 
to continue treatment in the presence of clinically stable or improved condition only after 
consultation with the principal investigator. 
 
 

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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 Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites are responsible for submitting data and/or data forms to the Office of 
Data Quality in accordance with DF/HCC SOPs. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information 
that raises any questions about participant safety or protocol performance will be addressed by 
the Overall PI, statistician and study team. Should any major concerns arise, the DSMB will 
offer recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; 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 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix H. 
• The Overall PI/Coordinating Center is responsible for distributing IND Action Letters or 
Safety Reports to all participating institutions for submission to their individual IRBs, if 
applicable   
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study 

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agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
12.4 
Collaborative Research and Future Use of Data and Biospecimens 
 
Tissue, blood, bodily fluids, and other materials derived from these will be collected in this study 
to analyze genes, DNA, RNA, proteins and cells for the study’s correlative endpoints and potential 
future research, utilizing new types of biomarker testing as it becomes available.  
 
These samples and any data generated as a part of these clinical trials may be used for future 
research studies and may be provided to collaborating investigators both within and outside of the 
DF/HCC for either correlative endpoints or secondary use. Samples and data may be shared with 
outside non-profit academic investigators, as well as with for-profit pharmaceutical investigators 
or commercial entities, with whom we collaborate. When samples or data are sent to collaborators 
and when any research is performed on them, all information will be identified with a code, and 
will not contain any PHI, such as name, birthday, or MRNs.  
 
In order to allow the greatest amount of research to be performed on the specimens and 
information generated as a part of this trial, researchers in this study may share results of genetic 
sequencing with other scientists. De-identified specimen or genetic data may be placed into one 
of more publicly-accessible scientific databases, such as the National Institutes of Health’s 
Database for Genotypes and Phenotypes (dbGaP). The results from the correlative research on 
this study will be shared with these public databases. Through such databases, researchers from 
anywhere will have access to de-identified samples or data for future research. More detailed 
information, beyond the public database, may only be accessed by scientists at other research 
centers who have received special permission to review de-identified data. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP). This document may modify the plans 
outlined in the protocol; however, any major modifications of the primary endpoint definition 
and/or its analysis will also be reflected in a protocol amendment. 
 
13.1 
Accrual and Sample Size Determination 
 
It is planned to stratify (as defined in Section 1.1) and randomize a total of 220 patients, in a 
1:2:1 ratio, to have 110 patients randomized to receive fulvestrant+palbociclib (arm B) and 55 
patients randomized to each of the control arm, fulvestrant (arm A), and the exploratory arm, 
fulvestrant+palbociclib+avelumab (arm C).  
 
An accrual duration of 30 months is expected, with accrual during the first 6 months averaging 
2.7 patients/month for a total of 16 patients while participating centers are activated, then 
uniform accrual of 8.5 patients per month for 24 months.  
 

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The sample size for the primary objective comparing fulvestrant+palbociclib versus fulvestrant 
(arm B versus arm A) was determined based on prior published experience of PALOMA-3 
[Cristofanilli et al, Lancel Oncol 2016] that the median PFS for patients receiving fulvestrant 
alone after prior endocrine therapy is estimated to be approximately 4 months, and a risk 
reduction by 38.5% (hazard ratio [HR]=0.6154) to a median PFS of 6.5 months (assuming 
exponential distribution of PFS) in the fulvestrant+palbociclib arm is a clinically-meaningful 
improvement in PFS with the combination. A total of 119 events are required to have 80% power 
to detect this improvement in PFS using a log-rank test with a one-sided alpha level of 0.05 and 
assuming 5% drop-out (i.e., PFS event never documented) by 6 months in each arm. Under the 
design assumptions, 119 PFS events in arms B+A would be expected after 32 months since start 
of enrollment. 
 
The sample size for the exploratory objective comparing fulvestrant+palbociclib+avelumab 
versus fulvestrant (arm C versus arm A) was determined based on the median PFS of 4 months 
for patients receiving fulvestrant alone, and a risk reduction by 47% (HR=0.53) to a median PFS 
of 7.5 months in the fulvestrant+ palbociclib+ avelumab is a clinically-meaningful improvement 
in PFS with triplet therapy. A total of 63 events are required to have 80% power to detect this 
improvement in PFS using a log-rank test with a one-sided alpha level of 0.05 and assuming 5% 
drop-out by 6 months in each arm. Under the design assumptions, after 32 months when the 
primary objective could be analyzed, 80 PFS events in arms C+A would be expected and power 
would be about 88%. 
 
13.2 
Analysis Populations 
 
Intent-to-Treat (ITT) Population: The ITT population will include all patients who are 
randomized, according to treatment assignment. The ITT population will be the primary 
population for evaluating all efficacy endpoints and patient characteristics. 
 
Safety Population: The safety population will include all patients who receive at least 1 dose of 
study treatment(s), according to actual study treatment received.  
 
13.3 
Analysis of Efficacy Endpoints 
 
Combination fulvestrant+palbociclib versus fulvestrant (arm B vs. arm A) 
 
For the primary objective, the distributions of PFS (as defined in Section 11.1.16) will be 
compared between fulvestrant+palbociclib versus fulvestrant (arm B versus arm A) using a 
stratified log-rank test with one-sided alpha level of 0.05. A stratified Cox proportional hazards 
model will be fitted to estimate the treatment hazard ratio and the corresponding two-sided 90% 
CI. The PFS distributions will be summarized according to treatment arm using the Kaplan-
Meier method and displayed graphically, along with estimates of median and other percentiles of 
the PFS distributions and with estimates of 6-month and 12-month PFS (with two-sided 90% CI 
to accompany each estimate).  
 
For the secondary objective, the OR rate (ORR) will be estimated according to treatment arm 
(fulvestrant+palbociclib versus fulvestrant ) as the number of patients with objective response (as 

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defined in Section 11.1.4.e) divided by the number of patients randomized to the respective 
treatment arm, with two-sided 90% CI for the ORRs. ORRs will be compared between the two 
treatment arms (arm B vs. arm A) using a Cochran-Mantel-Haenszel test with the same 
stratification factor as for the PFS analysis. 
 
Secondary measures based on radiological assessments of tumor burden (as defined in Sections 
11.1.4.e  and 11.1.5) will also be estimated and summarized according to treatment arm. Among 
the subset of patients with objective response, duration of response will be summarized using the 
Kaplan-Meier method. Best overall response will be summarized descriptively; the percent 
change in tumor burden corresponding to best overall response may be summarized graphically 
as a waterfall plot. Clinical benefit rate will be estimated and summarized similarly to ORR.  
 
As secondary and exploratory objectives, the treatment effects on PFS and OR will be estimated 
in subgroups defined according to predefined molecular subgroups, including ESR mutation, 
PI3K mutation, loss of Rb gene and/or function, and the stratification factor of whether or not 
there was exposure to a chemotherapy regimen between initial exposure to CDK4/6 inhibitor and 
entry on this study. In addition to HR and ORR estimates (with CIs), the p-value for test of 
subgroup-by-treatment interaction from Cox PH and logistic regression models will be reported 
though power for test of interaction is limited. 
 
For the primary endpoint, PFS is based on traditional RECIST 1.1 criteria with date of 
progressive disease (PD) as first radiologic evidence of PD. Per section 11.2.6, for any subject in 
Arm C who showed first radiologic evidence of progressive disease (PD) by RECIST 1.1 and is 
deemed clinically stable, it is at the discretion of the investigator to continue treating the subject 
until progression is confirmed at least 4 weeks from the date of first radiologic evidence of PD. 
 
Palbociclib after fulvestrant (arm A crossover) 
 
For the secondary objective to assess PFS and ORR with the addition of palbociclib after 
progression on fulvestrant alone, the analysis will include the subset of patients from the ITT 
population for arm A who initiate palbociclib after progression on fulvestrant alone. The PFS 
distribution will be summarized using the KM method, and the ORR will be estimated as the 
number of patients with objective response divided by the number of patients who initiate 
palbociclib after progression on fulvestrant alone. 
 
Fulvestrant+palbociclib+avelumab versus fulvestrant (arm C vs. arm A) 
For the exploratory objective to assess PFS and ORR for fulvestrant+palbociclib+avelumab 
versus fulvestrant alone, the analyses will follow as described above for the comparison of arms 
B vs. A.  
 
Fulvestrant+palbociclib+avelumab versus fulvestrant+palbociclib (arm C vs. arm B) 
 
For the exploratory objective to assess PFS and ORR for fulvestrant+palbociclib+avelumab 
versus fulvestrant+palbociclib, the analyses will follow as described above for the comparison of 
arms B vs. A, however the focus will be on estimation of treatment effects rather than testing. 
 

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13.4 
Comparison of RECIST versus irRC (arm C) 
 
As an exploratory objective, among patients assigned to fulvestrant+palbociclib+avelumab (arm 
C), the best overall response assessments by RECIST and irRC will be cross-tabulated to 
summarize concordance/discordance of the two assessments. Details of the cases of discordance 
will be described. 
 
13.5 
Safety 
 
The maximum grade of each adverse event (AE) type will be summarized as frequency (and %) 
of patients experiencing the AE, tabulated according to body system and AE type, separately 
according to treatment group. The summaries may be without regard to relation and in the subset 
considered as related to study treatment(s). Laboratory data will be summarized descriptively by 
cycle and treatment. 
 
Supplemental Safety Monitoring of Fulvestrant+Palbociclib+Avelumab (Arm C) 
 
In addition to regular reporting of AEs to the DSMB, sequential boundaries will be used to 
monitor safety of patients receiving fulvestrant+palbociclib+avelumab (arm C) in case of 
unexpectedly high treatment-related grade 3-5 non-hematologic AE rate, providing guidance to 
pause enrollment to arm C for further safety review if excessive numbers of these AEs are 
observed. The criteria are defined such that the probability of pausing is at most 0.05 if the true 
rate of these AEs is 33%, and the probabilities of pausing are  0.71 or  0.98 if the true rates are 
50% or 60%74. . The Table gives the criteria for pausing enrollment to arm C in order to more 
fully evaluate safety. 
 
Table. Criteria for pausing enrollment because of all/treatment-related grade 3-5 non-
hematologic AEs to more fully evaluate safety, for sample size up to 55 patients in arm C, with 
0.05 probability of pausing when the true AE rate is 33% (pause if number of AEs is ≥bn of N 
patients in the safety-evaluable population)  
 
Boundary (bn) 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
N pts in safety-
eval. population 
5 
6-7 
8-9 
10-
11 
12-
13 
14-
15 
16-
17 
18-
19 
20-
22 
23-
24 
25-
26 
27-
29 
30-
31 
32-
33 
34-
36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Boundary (bn) 
20 
21 
22 
23 
24 
25 
26 
27 
 
 
 
 
 
 
 
N pts in safety-
eval. population 
37-
38 
39-
40 
41-
43 
44-
45 
46-
48 
49-
50 
51-
53 
54-
55 
 
 
 
 
 
 
 
 
The safety-evaluable population will include patients randomized to arm C for whom AEs of at 
least the first cycle of protocol therapy have been recorded in the database or an SAE has been 
reported.  
 
13.6 
Interim Efficacy/Inefficacy Monitoring 
 
The study is designed to have one interim analysis and the final analysis for the primary 
objective, on the basis of the primary endpoint of PFS. The purpose of the interim analysis is to 

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allow early stopping of the study for futility. The interim analysis will be planned to correspond 
to the DSMB meeting after 50% of PFS events have been recorded, using the linear inefficacy 
boundary approach LIB2075. Under the design assumptions, 60 PFS events in arms B+A would 
be expected after 21 months since start of enrollment, at which point about 70% of enrollment 
would be expected 
13.7 
Correlative Objectives 
 
The analyses of correlative objectives will include descriptive and graphical summaries of the 
frequency and distribution of molecular events (specifically Rb loss or loss of function mutation, 
ESR mutation, PI3K mutation) and of copy numbers, proteins,  and RNA expression levels. 
Categorical biomarkers will be presented as number and percent with CIs; continuous 
biomarkers will be presented as mean, SD and CIs and as quartiles.  
 
The association of pre-treatment biomarkers will be explored in relation to PFS and OR using 
Cox and logistic regression, respectively. Most analyses will be conducted separately according 
to treatment group, and will focus on estimation of hazards and odds ratios with CIs rather than 
hypothesis testing. For analyses exploring predictive value of a biomarker, the test of treatment-
by-biomarker interaction will be reported. In consideration of statistical power for these analyses, 
the table summarizes detectable effect sizes (hazards ratios) for a range of binary biomarker 
prevalence for the three treatment groups separately, and assuming 100% or 80% biomarker data 
availability. Statistical power will be limited for tests of interaction and power will be estimated 
just prior to analysis on the basis of the observed numbers of patients and events, marker 
prevalence and average marker hazard ratio in order to guide interpretation of the tests.  
  
Table. Statistical power considerations for association of binary biomarkers with PFS, for the 3 
treatment groups separately and a range of biomarker prevalence, assuming 100% or 80% 
biomarker data availability. 
 
 
Detectable Hazard Ratios* 
 
 
Prevalence of binary variable 
N Pts 
N events 
0.10 
0.25 
0.33 
0.50 
110 
75 
3.0 
2.1 
2.0 
1.9 
55 
44 
4.0 
2.6 
2.4 
2.3 
55 
36 
4.7 
3.0 
2.7 
2.5 
88 
60 
3.4 
2.3 
2.2 
2.1 
44 
35 
4.7 
3.0 
2.7 
2.6 
44 
29 
5.7 
3.4 
3.0 
2.9 
Calculated with 2-sided α=0.05, 80% power    
 
Pre-treatment cyclin E levels will be summarized overall and according to whether or not there 
was chemotherapy exposure between initial CDK4/6 inhibitor exposure and entry on the study 
(stratification factor). Hypothesis testing will use Wilcoxon rank sum test with 2-sided α=0.05 to 
compare levels between exposure groups. Because the exposure group sizes are unknown we 
considered statistical power for alternative scenarios. For the most statistically-advantageous 
scenario in which 50% have and do not have chemotherapy exposure, there is >90% power to 
detect an 0.5 SD difference between exposure groups with either 110/group, or more 
conservatively with 88/group (assuming ~80% biomarker availability); power remains >80% if 
the exposure groups are instead two-thirds and one-third of patients enrolled.  

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14. PUBLICATION PLAN 
It is understood that any manuscript or releases resulting from the collaborative research will be 
circulated to all participating sites prior to submission for publication or presentation. The Primary 
Investigator will be the final arbiter of the manuscript content.   
The outcome results of this trial will be made public within 24 months of the end of data collection. 
Interim results of this trial may also be periodically presented at meetings of the American Society 
of Clinical Oncology and the San Antonio Breast Cancer Symposium.  Results of the formal 
interim analysis will be made available for presentation after analysis is complete. A full report of 
the outcomes will be made public no later than two (2) years after the end of data collection. 
 
 

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29. Finn RS, Dering J, Conklin D, et al: PD 0332991, a selective cyclin D kinase 4/6 inhibitor, 
preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer 
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30. DeMichele A, Sanders Clark A, Heitjan D, et al: A phase II trial of an oral CDK 4/6 inhibitor, 
PD0332991, in advanced breast cancer. J Clin Oncol 31 suppl:abstr 519, 2013 
31. Slamon DJ, Hurvitz SA, Applebaum S, et al: Phase I study of PD 0332991, cyclin-D kinase 
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33. Rock EP, Kennedy DL, Furness MH, et al: Patient-reported outcomes supporting anticancer 
product approvals. J Clin Oncol 25:5094-9, 2007 
34. Fromme EK, Eilers KM, Mori M, et al: How accurate is clinician reporting of chemotherapy 
adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life 
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35. Basch E, Jia X, Heller G, et al: Adverse symptom event reporting by patients vs clinicians: 
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care: comparing patient and physician assessments. Eur J Cancer 42:1159-66, 2006 
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ratings as predictors of overall cancer survival. J Natl Cancer Inst 103:1851-8, 2011 
38. Aaronson N, Ahmedzia S, Bergman B, et al: The European Organization for Research and 
Treatment for Cancer QLQ C-30: A quality of life instrument for use in international clinical 
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39. Osoba D, Zee B, Peter J, et al: Psychometric properties and responsiveness of the EORTC 
Quality of Life Questionnaire (QLQ C-30) in patients with breast, ovarian and lung cancer. 
Quality of Life Research 3:353-364, 1994 
40. Mendoza TR, Wang XS, Cleeland CS, et al: The rapid assessment of fatigue severity in 
cancer patients: use of the Brief Fatigue Inventory. Cancer 85:1186-96, 1999 
41. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 
years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: 
ATLAS, a randomised trial. Lancet 381:805-16, 2013 
42. Flaherty KT, Lorusso PM, Demichele A, et al: Phase I, dose-escalation trial of the oral 
cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in 
patients with advanced cancer. Clinical cancer research: an official journal of the American 
Association for Cancer Research 18:568-76, 2012 
43. FINAL REPORT, Sponsor Reference No. 12LJ025, A 15-Week Toxicity Study of PD-
0332991 by Oral Gavage Administration in Rats with a 4-Week Recovery Period, 
SPONSOR: Pfizer Worldwide Research and Development Drug Safety Research & 
Development 
44. Fribbens C, O'Leary B, Kilburn L, et al: Plasma ESR1 Mutations and the Treatment of 
Estrogen Receptor-Positive Advanced Breast Cancer. J Clin Oncol 34:2961-8, 2016 
45. Gradishar WJ, Anderson BO, Balassanian R, et al: NCCN Guidelines Insights: Breast 
Cancer, Version 1.2017. J Natl Compr Canc Netw 15:433-451, 2017 
46. Jeselsohn R, Buchwalter G, De Angelis C, et al: ESR1 mutations-a mechanism for acquired 
endocrine resistance in breast cancer. Nat Rev Clin Oncol 12:573-83, 2015 
47. Lehmann BD, Bauer JA, Chen X, et al: Identification of human triple-negative breast cancer 
subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750-67, 
2011 
48. Mittendorf EA, Philips AV, Meric-Bernstam F, et al: PD-L1 expression in triple-negative 
breast cancer. Cancer Immunol Res 2:361-70, 2014 
49. Nanda R, Chow LQ, Dees EC, et al: Pembrolizumab in Patients With Advanced Triple-
Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol 34:2460-7, 2016 

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50. Rugo HS, Rumble RB, Macrae E, et al: Endocrine Therapy for Hormone Receptor-Positive 
Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 
34:3069-103, 2016 
51. Schiavon G, Hrebien S, Garcia-Murillas I, et al: Analysis of ESR1 mutation in circulating 
tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl 
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52. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL.: SHP-1 and SHP-2 associate with 
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53. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and 
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55. Bennett F, Luxenberg D, Ling V, Wang IM, Marquette K, Lowe D, Khan N, Veldman G, 
Jacobs KA, Valge-Archer VE, Collins M, Carreno BM. Program death-1 engagement upon 
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56. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF. PD-L1/B7H-1 
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Zhu G, Tamada K, Chen L. Blockade of B7-H1 and PD-1 by monoclonal antibodies 
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tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 
blockade. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7.  
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immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2005 
Feb;17(2):133-44.  
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Yagita H, Azuma M, Nakajima Y. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin 
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APPENDIX A: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS CRITERIA 
 
Description 
Grade 
Fully active, able to carry on all pre-disease performance 
without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature, 
i.e., light house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry 
out any work activities.  Up and about more than 50% of 
waking hours. 
2 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
3 
Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
4 
 
 
 
 
 
 
 
 
 
 
 

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

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APPENDIX C: PALBOCICLIB DRUG DIARY  
Participant Identifier: _________________ 
Cycle Number:__________ 
Your MD: ___________________________ 
Phone: _________________ 
Your RN: ___________________________ 
Phone: _________________ 
 
Palbociclib Instructions 
How much: Your dose is __________________________ 
 
When: You should take your dose within 1 hour of a meal at the same time each day. 
 
Special Instructions 
If it is more than 6 hours after your regularly scheduled time, do not take that days dose. 
If you inadvertently take 1 extra dose during a day, you must skip the next days dose. 
If you vomit your dose, do not retake the dose. 
The Palbociclib is to be swallowed whole, and not to be chewed, crushed or opened. 
Please avoid eating grapefruit.  
Remember to bring any unused drug, all empty containers, and this diary with you to your next visit. 
 
Palbociclib Dosing Log 
 
Date 
Amount Taken 
Time Taken 
Taken within 1 hr of a meal 
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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APPENDIX D: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(VERSION 4.0) 
 
Cancer Therapy Evaluation Program, NCI CTCAE v 4.0. Available from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev 4.pdf. 
 
 

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APPENDIX E: RESEARCH SPECIMEN COLLECTION GUIDELINES 
 
Research Biopsy Guidelines 
Tissue specimens will be collected from recurrent or metastatic lesions using standard 
institutional procedures. 
 
The amount of tissue collected will follow the guidelines listed below: 
 
• Breast: A goal of 4-6 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 4-6 core biopsy specimens will be obtained using an 18-gauge 
needle. 
 
• Liver: A goal of 4-6 core biopsy specimens will be obtained using an 18-gauge needle. 
 
• Lung: Because of the risk of pneumothorax associated with core needle biopsies of lung 
nodules, no core biopsies of lung nodules will be performed on this protocol; unless if they 
are clinically indicated. 
 
• Bone: Because the yield of malignant tissue from bone biopsies tends to be relatively low, if 
a patient has another accessible site of disease (i.e. skin, lymph node, liver), that site should 
be biopsied preferentially. If bone is the only biopsy-accessible site, then a goal of 3-6 core 
biopsy specimens will be obtained using an 11-13 gauge needle. 
 
• Pleural Fluid: A goal of 300 cc of pleural fluid will be obtained with a standard thoracentesis 
procedure, with or without image guidance, according to the clinical judgment of the treating 
physician and clinician performing the procedure. Less than the goal amount is acceptable, 
and should be based upon the clinical judgment of the Investigator and the clinician 
performing the procedure. If more than the goal amount of fluid is obtained, then the entire 
specimen (with the exception of what is needed for clinical purposes, if applicable) will be 
stored in the tissue bank. 
 
• Ascites fluid: A goal of 300 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. 
 
Please note that the above are guidelines for the amount of tissue to be obtained, and are 
not meant to replace clinical judgment at the time the procedure is performed. Less than the 

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goal quantity of tissue is accepted for each type of biopsy, and will be left to the clinical 
judgment of the physician performing the procedure. If ascites or pleural fluid is to be used as the 
investigational biopsy specimen, consideration should be given to confirming the malignant 
nature of the ascites or pleural fluid prior to study entry. 
 
If a patient is undergoing resection of a lesion for clinical reasons (i.e. wedge resection of a 
new lung lesion for confirmation of diagnosis or re-testing of hormone receptor or HER2 status; 
or, resection of a chest wall lesion; or, resection of a lymph node), then the patient may opt to 
have a portion of that tissue (roughly equivalent to the goal amount of tissue listed in the 
guidelines above) stored for research at the time of the procedure  
 
Tissue Biopsy Handling and Processing 
Following research biopsy of a specimen, 2 tissue cores will be placed in formalin. The formalin 
biopsy samples should be kept at room temperature when stored and shipped ambient.  
. The other solid cores will be snap-frozen in OCT for future whole exome sequencing and 
RNAseq. The OCT cores will be stored in –80°C freezer until ready for shipment. OCT samples 
will be shipped frozen on dry ice as soon as possible. A unique sample identifier will be assigned 
to each sample and all other subject identifiers will be removed.   The preferred method for 
processing fluid samples is to generate pellets at the study site and shipped frozen to DFCI. If 
pellets are not feasible, the fluid may be decanted and stored in permanent centrifuge tubes in a 
minimum of 50 cc to a maximum of 150 cc (use up to three 50 mL centrifuge tubes). The fluid 
tubes should be placed upright in –80°C freezer until ready for shipment. 
 
 
Archival Tissue Collection 
1 paraffin-embedded tissue block + 1 H&E slide or 15-20 unstained slides + 1 H&E slide from a 
metastatic biopsy or surgery will be submitted to DFCI for gene profiling. If tissue from a 
metastatic procedure is not available, a sample from a primary breast cancer procedure may be 
submitted.  

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APPENDIX F: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA AND SAFETY MONITORING PLAN 
 
 

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TABLE OF CONTENTS 
1. INTRODUCTION 
 
1.1 
Purpose 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
2.1 
DF/HCC Sponsor 
2.2 
Coordinating Center  
2.3 
Participating Institution 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
3.1 
Protocol Distribution 
3.2 
Protocol Revisions and Closures 
3.3 
Informed Consent Requirements 
3.4 
IRB Documentation 
3.5 
IRB Re-Approval 
3.6 
Participant Confidentiality and Authorization Statement  
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
3.8 
DF/HCC Protocol Case Number 
3.9 
Safety Assessments and Toxicity Monitoring 
3.10 
Data Management 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
 
5. MONITORING: QUALITY CONTROL 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
5.2 
Monitoring Reports 
5.3 
Accrual Monitoring 
 
6. AUDITING: QUALITY ASSURANCE 
 
6.1 
DF/HCC Internal Audits 
6.2 
Audit Notifications 
6.3 
Audit Reports  
6.4 
Participating Institution Performance 
 
 

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1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The 
DF/HCC DSMP serves as a reference for any sites external to DF/HCC that are participating in a 
DF/HCC clinical trial. 
 
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.        
 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH) responsible for the coordination, development, submission, and approval of a protocol as 
well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, 
Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  The Lead 
Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also typically serves 
as the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes 
responsibility for initiation, management and conduct of the protocol at all research locations. In 
applicable protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies. The DF/HCC Sponsor has ultimate authority over the protocol and is responsible for the 
conduct of the study at DF/HCC and all Participating Institutions. In most cases the DF/HCC 
Sponsor is the same person as the DF/HCC Overall Principal Investigator; however, both roles can 
be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  The 
Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order 
that he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 

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specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol.  
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-
quality standards are used for data collection and the ongoing management of clinical trials, 
auditing, and data and safety monitoring. ODQ also coordinates quality assurance efforts related 
to multi-center clinical research. 
 
DF/HCC Research Informatics Office (RIO): A group within DF/HCC responsible for 
providing a comprehensive data management platform for managing clinical trial data. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities:  
 
2.1 
DF/HCC Sponsor 
 
The DF/HCC Sponsor, Erica Mayer, MD, MPH, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate 
protocol training (and/or a Site Initiation Visit prior to enrolling participants) and 
throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language understandable 
to all applicable site personnel when English is not the primary language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable reporting 
requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA, as applicable. 
• Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone other 
than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.  
 
2.2 
Coordinating Center  

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The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS). 
• Distribute protocol and informed consent document updates to Participating Institutions as 
needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation 
submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely 
review and submission to the DFCI IRB, as necessary.  
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI 
IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but is not 
limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federalwide Assurances (FWAs) for all sites,  all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites 
• Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc) and maintain documentation all relevant communications. 
 
2.3 
Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations and 
DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial as 
required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research related 
activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements 
• Submit protocol deviations and violations to local IRB per institutional requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements. 

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• Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
 
3.1 
Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.    
 
3.2 
Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its IRB 
of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 90 
days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect 
lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval. 
 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating Center, 
will update the Participating Institutions on an ongoing basis about protocol accrual data 
so that they will be aware of imminent protocol closures. 
 
3.3 
Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the DF/HCC 

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Guidance Document on Model Consent Language for PI-Initiated Multi-Center Protocols.  This 
document will be provided separately to each Participating Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician members 
of the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. Participating institutions must follow the DF/HCC requirement that only attending 
physicians obtain informed consent and re-consent for all interventional drug, biologic, or device 
research.   
 
3.4 
IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
3.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to continue 
research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.   
 
 
3.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information known as 
the Health Insurance Portability and Accountability Act (HIPPA). Any information, related to the 
physical or mental health of an individual is called Protected Health Information (PHI). HIPAA 
outlines how and under what circumstances PHI can be used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement.  This authorization statement 
may or may not be separate from the informed consent document.  The Coordinating Center, with 
the approval from the DFCI IRB, will provide a consent template, with information regarding 
authorization for the disclosure of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be 

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collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather 
than limited data sets with data use agreements. 
 
 3.6.1 DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned protocol case number (as 
described below) be used for all participant specific documents. Participant initials may be 
included or retained for cross verification of identification.  
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
  
 3.7.1 Participant Registration and Randomization  
 
Please refer to Protocol Section 4 for participant registration information. Treatment 
cannot begin until site has received confirmation that participant has been registered with 
DF/HCC CTMS.   
 
 3.7.2 Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific 
interventions may not be initiated until the Participating Institution receives confirmation 
of the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
 3.7.3 Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval 
will be permitted. All Participating Institutions are required to fully comply with this 
requirement. The process for requesting an eligibility exception is defined below. 
 
3.8 
DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, date of 
birth, gender, race and ethnicity. Once eligibility has been established and the participant 
successfully registered, the participant is assigned a unique protocol case number.  Participating 
Institutions should submit all de-identified subsequent communication and documents to the 
Coordinating Center, using this case number to identify the subject.   
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 

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participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB. 
 
3.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
 
 3.8.3 Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original submission.  
The deviation may not be implemented without all required approvals. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will 
forward all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 
 

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3.9 
Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, rights and 
well-being of study participants. Recording and reporting of adverse events that occur during the 
course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated therapy will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol Section 7.3. 
 
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their institutional 
policies and procedures 
 
3.9.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements and 
ensure that all IND Safety Reports are distributed to the Participating Institutions as 
required by DF/HCC policy. Participating Institutions will review/submit to their IRB 
according to their institutional policies and procedures. 
 
 
3.10 
Data Management 
 
DF/HCC RIO develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC RIO provides a web-based training for all 
eCRF users. 
   
3.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 

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a written or electronic query from the DF/HCC Office of Data Quality, Coordinating 
Center, or designee.  
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the 
case of a written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response.   
 
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms.  
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
 
The ordering of investigational agent is specified in the protocol Section 8.  
 
Participating Institutions should order their own agent regardless of the supplier.  
 
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the 
agent can be ordered once the protocol is approved by the local IRB.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the agent 
according to state and federal requirements. The local IRB should be kept informed of who will 
supply the agent (i.e., NCI or a pharmaceutical company) so that any regulatory responsibilities 
can be met in a timely fashion.  
 
5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides 
quality control oversight for the protocol. 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that Participating 
Institutions are complying with regulatory and protocol requirements, data quality, and participant 
safety. Monitoring practices may include but are not limited to source data verification, and review 
and analysis of eligibility requirements, informed consent procedures, adverse events and all 
associated documentation, review of study drug administration/treatment, regulatory files, 
protocol departures reporting, pharmacy records, response assessments, and data management.  

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Additionally, a plan will be formulated to provide regular and ongoing communication to 
Participating Institutions about study related information which will include participation 
in regular Lead Institution initiated teleconferences. Teleconferences will occur every 2 
weeks and will continue regularly until completion of accrual. Upon completion of 
accrual, teleconferences will occur monthly until all patients complete protocol therapy. 
Upon completion of protocol therapy, teleconferences will occur every 3 months until study 
completion. Additional communication may be distributed via “Newsletter” or email as deemed 
appropriate by DF/HCC Sponsor. 
 
On-Site Monitoring: On-site monitoring will occur on an as-needed basis. Participating 
Institutions will be required to provide access to participants’ complete medical record and source 
documents for source documentation verification during the visit. In addition, Participating 
Institutions should provide access to regulatory documents, pharmacy records, local policies 
related to the conduct of research, and any other trial-related documentation maintained by the 
Participating Site. On-site monitoring visits can be substituted with remote (virtual) monitoring 
visits at the discretion of the Principal Investigator.  
 
Remote Monitoring: Remote monitoring will be performed on an as-needed basis by the Clinical 
Trial Monitor. Sites will be asked to provide source documentation via fax, email, or mail as 
specified by the Clinical Trial Monitor for virtual monitoring. 
 
5.2 
Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that are 
unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations.  
 
5.3 
Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination. 
 
A minimum of 3 participants per site annually is recommended for Phase II trials. However, 
given the additional regulatory burden and cost of overseeing each site, a consideration of 5 per 
site/annually should be a minimum target for each site. 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated activities 
were appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, applicable Standard Operating Procedures (SOPs), and the 
Code of Federal Regulations (CFR). 

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6.1 
DF/HCC Internal Audits 
  
 All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2 day period. If 
violations which impact participant safety or the integrity of the study are found, more participant 
records may be audited.  
 
6.2 
Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all scheduled 
audit dates (internal or NCI) and re-audit dates (if applicable), which involve this protocol. All 
institutions will forward a copy of final audit and/or re-audit reports and corrective action plans (if 
applicable) to the Coordinating Center, within 12 weeks after the audit date.  
 
6.3 
Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if applicable. 
The Coordinating Center, must forward any reports to the DF/HCC ODQ per DF/HCC policy for 
review by the DF/HCC Audit Committee. For unacceptable audits, the DF/HCC Audit Committee 
would forward the final audit report and corrective action plan to the DFCI IRB as applicable. 
 
6.4 
Participating Institution Performance 
 
The DF/HCC Sponsor, with the DFCI IRB, charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its responsibilities 
as described above.