Clinical trial NCT02499120
Conditions: Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Keywords: palbociclib, cetuximab, human papillomavirus, squamous cell carcinoma, head and neck cancer
Sponsor: Pfizer
Start date: 2015-09-10; Completion date: 2022-09-07
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether the combination of palbociclib with cetuximab is superior to cetuximab in prolonging overall survival in HPV-negative, cetuximab-naive patients with recurrent/metastatic squamous cell carcinoma of the head and neck.

Detailed description:

Arms: arm 1: Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle; in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes. arm 2: Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle; in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.
Interventions: intervention 1: palbociclib intervention 2: Cetuximab intervention 3: Placebo
Intervention descriptions: intervention 1: Palbociclib will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib free base. Administered with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle. intervention 2: Cetuximab injection for IV infusion will be provided in 100 mg/50 mL, single-use vials, and 200 mg/100 mL, single-use vials. In Japan, cetuximab will be provided in 100 mg/20 mL, single-use vials. Administered, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes. intervention 3: Placebo for palbociclib will be indistinguishable from the palbociclib capsules and will be supplied as capsules matching in size and color the various palbociclib formulations.

Administered with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle.

Protocol documents:
Prot_001.pdf: 
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A RANDOMIZED, MULTICENTER, DOUBLE-BLIND PHASE 2 STUDY OF 
PALBOCICLIB PLUS CETUXIMAB VERSUS CETUXIMAB FOR THE 
TREATMENT OF HUMAN PAPILLOMAVIRUS-NEGATIVE, 
CETUXIMAB-NAÏVE PATIENTS WITH RECURRENT/METASTATIC 
SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK AFTER FAILURE 
OF ONE PRIOR PLATINUM-CONTAINING CHEMOTHERAPY REGIMEN
Compound:
PD-0332991
Compound Name:
Palbociclib
US IND Number:
122168
European Clinical Trial Database 
(EudraCT) Number:
2015-000515-41
Protocol Number:
A5481044
Phase:
2


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Document History
Document
Version Date
Summary of Changes
Amendment 2
31 March 2016
1. Schedule of Activities/Tumor Assessment 
Requirements Flowchart: 29Jul2015 PCL 
removal of the phrase “on Day 1 of even cycles” 
for Disease Assessment to align with 
Sections 7.1.1, Tumor Assessments.
2. Schedule of Activities, footnote c/Section 6.2, 
Active Treatment Phase: Add vital signs for any 
new cycle Day 1 procedures.
3. Schedule of Activities, footnote l/Section 6.3, 
End of Treatment Visit/Section 7.3.1, Laboratory 
Safety Assessments: included patients starting 
post-study anticancer therapy for 8 week 
chemistry panel analysis.
4. Schedule of Activities, footnote n
/Abbreviations/Section 7.3.1, Laboratory Safety 
Assessments: 21Oct2015 PCL added aPTT as 
acceptable coagulation parameter.
5. Schedule of Activities, footnote y/Section 5.8, 
Concomitant Treatments: Added further 
clarification for patients beginning new therapy 
before the 28-day time period is complete.
6. Schedule of Activities, footnote z/Section 7.7, 
Patient Reported Outcomes: Added further 
clarification for patients starting post-study 
anticancer therapy.
7. Tumor Assessment Requirments Flowchart, 
footnote d/Section 7.1.1 Tumor Assessment: 
Removed the phrase “and pelvis”.
8. Section 4.2 Exclusion Criteria: Removed the 
phrase “or requirement for a feeding tube” and 
clarified inability to swallow capsules for
Exclusion Criterion # 5.
9. Section 4.4 Lifestyle Guidelines: Added phrase to 
template language referencing inclusion 
criterion # 8.
10. Section 5.4.2.2, Cetuximab: 23April2015 PCL 
update to align with Section5.4.1.3 verbiage.


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Document
Version Date
Summary of Changes
11. Section 5.5.1, Palbociclib/Placebo/Section 5.5.2, 
Cetuximab: 16Oct2015 PCL added verbiage to 
align with Single Reference Safety Documents 
for monitoring the patient during study drug 
administration.
12. Section 5.5.2, Cetuximab/Section 5.8.2, 
Medications not Recommended: 14Jan2016 PCL 
added instruction to administer corticosteroid 
premedication to align with Single Reference 
Safety Document, Summary of Product 
Characteristics for cetuximab.
13. Section 5.5.3.1.3 Cetuximab Dermatological 
Toxicities: Removed the phrase “topical 
corticosteroids are not recommended”.
14. Section 5.5.3.4, Palbociclib/Placebo Dose 
Reductions: Clarified patients requiring more 
than 2 dose reductions will be discontinued from 
palbociclib/placebo treatment.
15. Section 7.1.1, Tumor Assessments: Corrected 
statement to state “secondary endpoint of PFS” in 
fourth sentence.
16. Section 7.4.1, Palbociclib/Placebo PK 
Assessments/Section 7.5, Biomarker 
Assessments: Added one day for the accepted 
range to make-up a missed PK draw.  Provided 
further instruction for makeup PK sampling 
 
.
17. Typos and grammatical errors corrected 
throughout the protocol. 
Amendment 1
09 April 2015
1. Protocol Summary/Study Design/ Tumor 
Assessment Requirements Flowchart/Sections 3 
Study Design, 7.1.1.2 Post-Baseline Tumor 
Assessments: Removed statement concerning 
continuous treatment beyond RECIST-defined 
disease progression (agreement between Sponsor 
and FDA).
2. Protocol Summary, Study Design/Section 3 Study 
Design/Section 4.3 Randomization 
Criteria/Section 5.1 Allocation to Treatment/9.2.1 
CCI


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Document
Version Date
Summary of Changes
Analysis of Primary Endpoint:  Clarified 
stratification terminology from checkpoint 
inhibitors to immunothereapy.
3. Schedule of Activities/Tumor Assessment 
Requirements Flowchart/Sections 7.1.1.1 
Screening/Baseline Tumor Assessments and 
7.1.1.2 Post-Baseline Tumor Assessments: Added 
CT or MRI scan of the chest and abdomen 
(including the liver) to support PFS secondary 
endpoint.
4. Clarification of Inclusion Criteria # 9 for patients 
aged 20 years old or greater as applicable by local 
country regulations.
5. Section 5.5.3.1.1 Cetuximab Hypersensitivity 
Reactions:  Simplified wording for cetuximab 
retreatment after Grade 2 hypersensitivity 
reactions.
6. Section 5.5.3.1.4 Cetuximab Gastrointestinal 
Adverse Events:  Added “Patients experiencing 
treatment-related Grade 4 vomiting or diarrhea 
should have their cetuximab and 
palbociclib/placebo treatments permanently 
discontinued.”
7. Section 5.5.3.2.1 Palbociclib/Placebo Dosing 
Interruptions/Delays:  Added “Patients 
experiencing treatment-related Grade 4 vomiting, 
diarrhea, or hypertension should have their 
palbociclib/placebo and cetuximab treatments 
permanently discontinued.”  Removed “≥” from 
Grade 3 non-hematologic bullet point (5th bullet 
point). Added bullet point “Grade 4 
non-hematologic toxicities (see exceptions of 
vomiting, diarrhea, or hypertension above).”
8. Section 5.5.3.3 Palbociclib/Placebo Retreatment: 
Added “Patients experiencing treatment-related 
Grade 4 vomiting, diarrhea, or hypertension 
should have their palbociclib/placebo and 
cetuximab treatments permanently discontinued.” 
Removed “≥” from Grade 3 non-hematologic 
bullet point (3rd bullet point).  Added bullet point, 
“Grade 4 treatment-related non-hematologic AEs 


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Document
Version Date
Summary of Changes
with the exception of alopecia, have recovered to 
Grade 1 or baseline (or, at the investigator’s 
discretion, Grade 2 if not considered a safety 
risk for the patient).  Patients experiencing 
treatment-related Grade 4 vomiting, diarrhea, or 
hypertension should have their 
palbociclib/placebo and cetuximab treatments 
permanently discontinued.”
9. Section 5.5.3.4 Palbociclib/Placebo Dose 
Reductions: Removed “” from Grade 3 non-
hematologic statement in Table 5 (fifth row). 
Added Grade 4 non-hematological toxicity row 
clarification.
10. Section 7.4.1 Palbociclib PK Assessments: 
Removed duplicate statement “…efforts should 
be made to coordinate biomarker and PK blood 
draws within a 30 minute window.”
11. Section 7.4.2 Cetuximab PK Assessment: Added 
“Blood samples for post-dose PK assessments of 
cetuximab should not be collected from the same 
arm that the cetuximab IV infusion was 
administered.”
12. Section 9.3.3 Patient-Reported Outcomes 
(PROs): Corrected tumor type to squamous cell 
carcinoma of the head and neck.
13. Typos and grammatical errors corrected 
throughout the protocol. 
14. Required Protocol Template updates in Adverse 
Event Reporting section and Communication of 
Results by Pfizer section.
Original protocol 06 March 2015
N/A
This amendment incorporates all revisions to date, including amendments made at the 
request of the United States Food and Drug Administration (USFDA).


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ABBREVIATIONS
Abbreviation
Term
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
bid
Bis in Die (twice a day)
CAG
Clinical Assay Group
CCND1
Cyclin D1
CDK
Cyclin-Dependent Kinase
CDKN2A, p16Ink4A
Cyclin-Dependent Kinase Inhibitor 2A
cf
Circulating-Free
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
CMH
Cochran-Mantel-Haenszel
CNS
Central Nervous System
CR
Complete Response
CRF
Case Report Form
CSA
Clinical Study Agreement
CT
Computed Tomography
CTA
Clinical Trial Application
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CxDy
Cycle x, Day y (refer to Schedule of Activities)
CYP
Cytochrome P-450
d
Day
DDI
Drug-Drug Interaction
dL
Deciliter
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
DU
Dispensable Unit
EC
Ethics Committee
ECG
Electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
E-DMC
External Data Monitoring Committee
EDP
Exposure During Pregnancy
EDTA
Ethylenediaminetetraacetic acid
EGFR
Epidermal Growth Factor Receptor
CCI


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EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire
EORTC-QLQ-H&N35
European Organisation for Research and Treatment of Cancer 
Head and Neck Module 35
ER
Estrogen Receptor
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration 
FDAAA
Food and Drug Administration Amendments Act
FFPE
Formalin-Fixed Paraffin Embedded
FSH
Follicle-Stimulating Hormone
g
gram
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
H1
Histamine Antagonist of the H1 Receptor
Hb
Hemoglobin
HDPE
High Density Polyethylene
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HPV
Human Papillomavirus
HR 
Hormone Receptor or Hazard Ratio (depending on context)
HRQL
Health-Related Quality of Life
HSR
Hypersensitivity Reaction
IB
Investigator’s Brochure
IC50
Concentration of 50% Inhibition 
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ID
Identification
IHC
Immunohistochemistry
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Randomization Technology or Interactive Response 
Technology (depending on context)
IUD
Intrauterine Device
IV
Intravenous
IVR
Interactive Voice Response
IWR
Interactive Web Response
L
Liter
LFT
Liver Function Test
LPLV
Last Patient Last Visit
m2
Square meter, also sqm
MedDRA
Medical Dictionary for Regulatory Activities


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mg
Milligram
MID
Minimally Important Difference
mIU
Milli-International Unit
mL
milliliter
mm3
Cubic millimeter
MRI
Magnetic Resonance Imaging
msec
millisecond
MTD
Maximum Tolerated Dose 
N/A
Not Applicable
NABSA
Nucleic Acid Sequence Based Amplification
NCI
National Cancer Institute 
NGS
Next-Generation Sequencing
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
PCD
Primary Completion Date
PCR
Polymerase Chain Reaction
PD
Progressive Disease, Progression of Disease, or 
Pharmacodynamic (depending on context)
PFS
Progression-Free Survival
PK
Pharmacokinetic 
PPI
Proton-Pump Inhibitor
PR
Partial Response or PR interval is measured from the beginning 
of the P wave to the beginning of the QRS complex (depending 
on context)
PRO
Patient-Reported Outcome
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QD
Quaque Die (once daily)
QOL
Quality of Life
QRS
The QRS complex is a name for the combination of three of the 
graphical deflections seen on a typical electrocardiogram.
The QRS complex reflects the rapid depolarization of the right 
and left ventricles
QT
Time between the start of the Q wave and the end of the T wave 
in the heart's electrical cycle
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett's fomula
QTcF
QT interval corrected for heart rate using Fridericia's fomula
RB/Rb
Retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
R/M
Recurrent/Metastatic
RNA
Ribonucleic Acid


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RP2D
Recommended Phase 2 Dose
RR
The interval between an R wave and the next R wave
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCCHN
Squamous Cell Carcinoma of the Head and Neck
SCL
Supply Chain Lead
SD
Stable Disease or Standard Deviation (depending on context) 
SOA
Schedule of Activities
SOC
System Organ Class
SPC
Summary of Product Characteristics
Sqm
Square meter, also m2
SRSD
Single Reference Safety Document
t½
Terminal Elimination Half-life 
TdP
Torsade de Pointes
Tmax
Time for Cmax
ULN
Upper Limit of Normal
US
United States
V
version
WBC
White Blood Cells
CC
I
CCI


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PROTOCOL SUMMARY
Indication:
Human papillomavirus (HPV)-negative, cetuximab-naïve, recurrent/metastatic (R/M) 
squamous cell carcinoma of the head and neck (SCCHN) after failure of one platinum-based 
chemotherapy regimen.
Background and Rationale:
SCCHN is the sixth most common cancer.  Globally, approximately 600,000 new cases occur 
yearly.  In the United States (US), it is estimated that about 55,000 new cases of oral cavity, 
pharyngeal, and laryngeal cancers will occur in 2014, which account for about 3% of new 
cancer cases. 
Epidermal growth factor receptor (EGFR) overexpression is found in approximately 90% of 
SCCHN cases, and it is associated with decreased progression-free survival (PFS) and 
overall survival (OS).  EGFR-directed drugs include antibodies that prevent ligand-binding 
and/or receptor dimerization (eg, cetuximab) and small molecule adenosine 
triphosphate-competitive inhibitors of the intrinsic catalytic activity of ErbB receptors
(eg, erlotinib and gefitinib). 
Important regulatory proteins involved in the cell cycle transition from G1 to the S-Phase are 
cyclin D1 (CCND1), p16INK4A (thereafter referred to as p16) and cyclin-dependent kinases
(CDKs). Deregulation of aspects of the cell-cycle, including CDKs, have been shown to 
contribute to the development of cancer. Overexpression of cyclin D1 and inactivation of 
p16 occur in the vast majority of cases of HPV-negative SCCHN.  Genomic characterization 
of oral SCCHN identified amplification of CCND1 and/or loss of CDKN2A (encoding p16 
protein) were found in 94% of tumors, supporting the observation that cell cycle alterations 
were a nearly universal feature.
Palbociclib is a highly selective, reversible oral inhibitor of cyclin-dependent kinases 4 and 6 
(CDK 4/6). The compound prevents cellular deoxyribonucleic acid (DNA) synthesis by 
prohibiting progression of the cell cycle from G1 into S phase.  In clinical trials, palbociclib
enhanced tumor response to letrozole in women with HR-positive, HER2-negative metastatic 
breast cancer.  Palbociclib also has efficacy in cyclin D1 overexpressing mantle cell 
lymphoma and has activity in a broad range of other solid tumors.
Combinatorial efficacy was observed following treatment with palbociclib and inhibitors of 
the EGFR pathway, including cetuximab, in preclinical models.  In a panel of 24 SCCHN 
cell lines the palbociclib combination with cetuximab produced synergistic growth inhibition 
in 50 % of models. The combination of palbociclib and cetuximab in a subset of these cell 
lines demonstrated increased inhibition of retinoblastoma protein and downstream
transcription factor E2F signaling, leading to greater inhibition of new DNA synthesis and 
increased hallmarks of cellular senescence than with each agent alone. In vivo studies in 
patient-derived xenografts demonstrated the ability of either single agent to produce 
>90% tumor growth inhibition in distinct models, and in a model that failed to show 
significant response to either single agent, the combination of palbociclib and cetuximab 
yielded synergistic tumor growth inhibition.


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In an ongoing Phase 1 clinical trial of escalating doses of palbociclib added to fixed-dose 
cetuximab, one partial tumor response was observed in a patient with SCCHN resistant to 
cetuximab and cisplatin.  Disease control (partial response [PR] or stable disease [SD]) 
occurred in 6 of the 7 evaluable patients. Of the 6 patients with cetuximab-resistant SCCHN, 
5 experienced disease control with combined palbociclib + cetuximab treatment. Of the 
4 patients with cisplatin-resistant SCCHN, 3 experienced disease control with palbociclib + 
cetuximab.
The current Phase 2 study provides the opportunity to test the hypothesis that the addition of 
palbociclib to cetuximab will improve outcomes in patients with platinum-resistant, incurable 
SCCHN in a direct, double-blind comparison to cetuximab.
Objectives:
Primary Objective:

To demonstrate that the combination of palbociclib with cetuximab is superior to
cetuximab in prolonging OS in HPV-negative, cetuximab-naïve patients with R/M 
SCCHN in whom one prior platinum-containing chemotherapy has failed.
Secondary Objectives:

To compare secondary measure of efficacy between the treatment arms;

To compare safety and tolerability between the treatment arms;  

To compare Patient-Reported Outcome (PRO) measures between the treatment arms;

To characterize the correlations between baseline biomarker (eg, p16, Rb) expression
in tumor tissue and clinical efficacy in both treatment arms;

To characterize steady state trough concentrations for palbociclib, and trough and 
maximum concentrations for cetuximib in patients with R/M SCCHN.
 
 
 
CCI


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Endpoints:
Primary Endpoint:  

Overall Survival.
Secondary Endpoints: 

Progression-Free Survival (PFS), Objective Response (OR), Duration of Response 
(DR), per RECIST v1.1, as assessed by investigator; 

Type, incidence, severity (as graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03), seriousness 
and relationship to study medications of adverse events (AEs) and any laboratory 
abnormalities;

PRO endpoints: European Organisation for Research and Treatment of Cancer 
Quality of Life Instrument (EORTC-QLQ-C30); European Organisation for Research 
and Treatment of Cancer Head and Neck Module 35 (EORTC-QLQ-H&N35);

Tumor tissue biomarkers by immunohistochemistry (IHC; p16 and Rb);

Trough concentrations at steady state for palbociclib; trough and maximum 
concentrations for cetuximib.
 
Study Design:
This is an international, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group Phase 2 study comparing the efficacy and safety of palbociclib in combination 
with cetuximab versus cetuximab in HPV-negative, cetuximab-naïve patients with R/M 
SCCHN after failure of one platinum-containing regimen.  Approximately 120 patients will 
be randomized 1:1 between the investigational arm (Arm A: palbociclib plus cetuximab) and 
the comparator arm (Arm B: placebo plus cetuximab).  Crossover between treatment arms 
will be prohibited.
C
C
I
CCI


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Patients will be stratified by Eastern Cooperative Oncology Group (ECOG) performance 
status (0 vs 1), and by prior use of immunotherapy (yes vs no).
Patients randomized to Arm A (investigational arm) will receive:

Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed 
by 7 days off treatment in a 28-day cycle; 
in combination with

Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion 
followed by 250 mg/m2 weekly infused over 60 minutes.
Patients randomized to Arm B (comparator arm) will receive: 

Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in 
a 28-day cycle; 
in combination with

Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 
250 mg/m2 weekly infused over 60 minutes.
Patients will continue to receive their assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.  
The importance of timely and complete disease assessments in this study cannot be 
overstated.  Disease assessments will be performed every 8 weeks (7 days) from the date of 
randomization.  Each assessment will be performed as scheduled according to the calendar 
regardless of any dosing delay to prevent the introduction of bias into the assessment of 
efficacy.  Failure to perform any of the required disease assessments will result in the 
inability to determine disease status for that time point.  Tumor assessments will be 
performed until radiographically and/or clinically (ie, for photographed or palpable lesions) 
documented progressive disease (PD) as per RECIST v.1.1, initiation of new anticancer 
therapy, or discontinuation of patient from overall study participation (eg, death, patient's 
request, lost to follow-up), whichever occurs first.  Off schedule or incomplete disease 
assessments have the potential to weaken the conclusion of this clinical trial and must be 
avoided wherever possible.
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented PD as per RECIST
v.1.1 will continue to have tumor assessment performed during the follow-up visits every 
8 weeks (7 days) until RECIST-defined disease progression, initiation of new anticancer 
therapy or discontinuation of patient from overall study participation (eg, death, patient's 
request, lost to follow-up), whichever occurs first. 


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Patients discontinuing the active treatment phase will enter a follow-up period during which 
survival and new anti-cancer therapy information will be collected every 2 months from the 
last dose of investigational product.  The follow-up period will conclude at the time of the
final OS analysis.
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as the primary data source.
Patients will undergo study-related safety, efficacy, and PK assessments as outlined in the
Schedule of Activities section.
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers assessed in tumor tissue and blood obtained prior to 
treatment for their potential predictive value in identifying patients who may benefit from 
treatment with cetuximab in combination with palbociclib or placebo. Blood and tumor 
(optional) biomarkers also assessed on-treatment provide an opportunity to investigate 
pharmacodynamics effects, and tumor specimen (optional) and blood collected upon disease 
progression (end of treatment) will be analyzed to investigate potential mechanisms of 
resistance to treatment.
In addition, blood samples will be collected from all patients in Cycles 1 and 2 to assess 
steady-state trough concentrations of palbociclib and pre- and post-infusion concentrations of 
cetuximab to provide an opportunity to conduct an exploratory exposure/response analysis 
for safety and efficacy findings as well as correlative analyses between drug exposure and 
biomarker changes from baseline.
Examining and measuring the patient’s subjective experience in this study will be 
accomplished using health-related quality of life questionnaires. These assessments provide 
the means to validly and reliably quantify subjective information, which is provided by the 
study patients in response to specific questions from validated instruments.  Observations
will be documented at specified timepoints throughout the study, plus 1 observation after 
treatment discontinuation (to measure the impact of progressive disease on the patient’s 
quality of life).
An independent third party External Data Monitoring Committee (E-DMC) will monitor the 
the efficacy and safety of patients in the study according to the Charter. The E-DMC will 
make recommendation as to whether or not the trial should continue based on ongoing 
reviews of safety data.  In addition, the E-DMC will also evaluate interim efficacy data and 
make a recommendation regarding study continuation based on observed results of the study.  
The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision.


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Statistical Methods:
The primary objective of this study is to demonstrate that the combination of palbociclib with 
cetuximab is superior to cetuximab in prolonging OS in the target population.  This study is 
designed to test the null hypothesis of equal survival between treatment arms versus the 
alternative hypothesis of improved survival in the palbociclib + cetuximab arm compared 
with the placebo + cetuximab arm.
Assuming a median OS of 6 months in the comparator arm, approximately 79 total events
(deaths) are required for 1:1 randomization to have at least 80% power to detect a true hazard 
ratio of 0.6 (corresponding to a median OS of 10 month in the palbociclib arm) using a 
one-sided, log-rank test at a significance level of 0.1.  One interim analysis based on OS is 
planned when at least 50% of the OS events (40 deaths) have been observed.  The purpose of 
this interim analysis is to provide an opportunity to potentially stop the study early for
futility.  The study may be considered for early termination if the hazard ratio estimate is 
greater than 0.9.  The formal futility boundary will be constructed using the Gamma family 
of spending function with parameter = 0.05.  With 40 observed events at the interim analysis, 
the futility boundary is p-value = 0.36 (corresponding to HR = 0.9). The boundary at final 
analysis is p-vlaue = 0.1.
Approximately 120 patients will be enrolled in about 16 months and followed for about 
6 months to observe the required number of events.  This estimation is based on the 
following assumptions on the enrollment rates: 1) 5 patients per month (on average) during 
the first 6 months; 2) 10 patients per month (on average) thereafter.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Study Procedures (Section 6)
and Assessments (Section 7) sections of the protocol for detailed information on each procedure and assessment required for 
compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the patient.
Schedule of Activities
Visit Identifier
Screening
Active Treatment Phasea (One Cycle = 28 
days)
End of Treatment 
/ Withdrawald
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-Upe
Cycles 1 and 2c
Cycles 3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1b
Day 15
Day 1c
Time Window
3d
3d
3d
7d
7d
7d
Baseline Documentation
Informed Consent Processf
X
Medical / Oncological Historyg
X
Baseline Signs / Symptomsh
X
Human Papillomavirus 
(HPV)-status analysisi
X
Physical Examination/Vital 
signsj
X
Xb
X
X
Serum Pregnancy Testk
X
X
X
X
ECOG Performance Status
X
X
X
X
Laboratory Studies
Hematologyl
X
Xb
X
X
X
Blood Chemistryl, m
X
Xb, m
X
X
X
X
Coagulationn
X
Xb
X
X
X
Urinalysisl
X
Xb
X
X
X
12-Lead ECG (in triplicate)o
X
Xb
(C1 only)
X
X (C4, C7, C10)
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Visit Identifier
Screening
Active Treatment Phasea (One Cycle = 28 
days)
End of Treatment 
/ Withdrawald
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-Upe
Cycles 1 and 2c
Cycles 3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1b
Day 15
Day 1c
Time Window
3d
3d
3d
7d
7d
7d
Special Laboratory Studies
 
Archival Tumor Tissue 
Specimenr
X
De Novo Tumor Specimenss
X
X
X
 
 
 
 
Disease Assessment 
Computed Tomography (CT)/ 
Magnetic Resonance Imaging 
(MRI) Scans of Head and Neck 
(oral cavity, oropharynx, 
hypopharynx, larynx), chest, 
abdomen (including the liver)
and any clinically indicated 
sites of disease; Clinical 
evaluation of superficial 
diseasev
X
◄--►
Performed every 8 weeks (7 days) from the 
date of randomization
X
X
Other Clinical Assessments 
Drug Compliancew
◄--►
Adverse Event (AE) Reportingx
X
X
X
X
X
X
X
X
Review Concomitant 
Medications/Treatmentsy
X
X
X
X
X
Quality of Life Questionnaire 
(EORTC-QLQ-C30 and 
EORTC-QLQ-H&N35) z
X
X
X
X
Survival Follow-up
X
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Visit Identifier
Screening
Active Treatment Phasea (One Cycle = 28 
days)
End of Treatment 
/ Withdrawald
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-Upe
Cycles 1 and 2c
Cycles 3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1b
Day 15
Day 1c
Time Window
3d
3d
3d
7d
7d
7d
Study Treatment
Randomization 
X
Cetuximab (both treatment 
arms)
◄--►
Weekly IV Infusion
Palbociclib or Placebo
◄--►
Once daily with food on Day 1 to Day 21 of 
each cycle followed by 7 days off
Abbreviations: ◄--►= ongoing/continuous event; AE = adverse event; 
 CT = computed tomography; CRF = case report form;
CxDy = Cycle x Day y; DNA = deoxyribonucleic acid; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; FFPE = formalin-fixed 
paraffin embedded; HPV = Human Papillomavirus; MRI = magnetic resonance imaging; SAE = Serious Adverse Event; WBC = white blood cells
a.
Active Treatment Phase: All assessments should be performed prior to dosing with study medications on the visit day unless otherwise indicated.  
Acceptable time windows for performing each assessment are described in the column headers. For the purposes of this trial, 1 cycle is 28 days in length. A 
cycle could be longer than 28 days if persistent toxicity delays the initiation of the subsequent cycle.
b.
Cycle 1/Day 1: Physical examination/vital signs, blood chemistry, hematology, urinalysis, coagulation, and 12-lead ECG are not required if acceptable 
screening assessment is performed within 7 days prior to randomization.
c.
Cycle X, Day 1: In the event that the start of a new cycle is delayed due to treatment related toxicity, procedures required on Day 1 of the given cycle will be 
performed when palbociclib/placebo is resumed.  New cycle Day 1 procedures (ie, physical examination, vital signs, ECOG performance status, ECG, 
Quality of Life questionnaires, blood chemistry, hematology, urinalysis, coagulation, and serum pregnancy test) that were performed prior to knowing the 
need to delay the start of the cycle do not need to be repeated (1) if not required to determine whether study drug may be resumed and (2) if performed 
within 7 days prior to study drug resumption.
d.
End of Treatment/Withdrawal: End of Treatment/Withdrawal visit will be performed as soon as possible but no later than 4 weeks (ie, 28 days) 7 days 
from last dose of study treatment and prior to the initiation of any new anticancer therapy.
e.
Post Treatment Follow-up:  After discontinuation of study treatment, post-treatment follow-up (including survival status and post-study anticancer therapy 
evaluation) will be collected every 2 months (7 days) from the last dose of study treatment.  Telephone contact is acceptable.
f.
Informed Consent: Informed consent may be obtained greater than 28 days from randomization; however, it must be obtained prior to any protocol 
required assessments being performed.
g.
Medical/Oncological History: To include information on prior anticancer treatments.
h.
Baseline Signs/Symptoms: Baseline tumor related signs and symptoms will be recorded at the C1D1 visit prior to initiating treatment and then reported as 
AEs during the trial if they worsen in severity or increase in frequency.
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i.
HPV-status: Patients must be HPV-negative to participate in this study.  Analytical method is per institutional standards.
j.
Physical Examination/Vital signs: A full physical examination including an examination of all major body systems (including head, ears, eyes, nose, 
mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and musculoskeletal), height (at screening only), weight, blood pressure and pulse rate, which 
may be performed by a physician, registered nurse or other qualified health care provider, will be required at Screening and C2D1.  If screening assessment 
is not performed within 7 days prior to randomization, a full physical examination must be performed at C1D1. Symptom-directed physical examinations, 
blood pressure and pulse rate assessments will be performed at subsequent visits.
k.
Serum Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, and assayed in a 
certified laboratory, will be performed on 2 occassions prior to starting study therapy- once at the start of screening, and once at the baseline visit, 
immediately before investigational product administration.  A negative pregnancy result is required before the patient may receive the investigational 
product.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected), repeated at Day 1 of each cycle, and at the end of the study to confirm the patient has not become pregnant during the study.  
Pregnancy tests may also be repeated as per request of institutional review boards (IRBs)/ethics committees (ECs) or if required by local regulations.  In case 
of a positive confirmed pregnancy, the patient will be withdrawn from study medication and from the study.  Two methods of highly effective contraception 
must be used throughout the study and continue for 6 months after the last dose of cetuximab.  See Section 4.4 for further information.
l.
Hematology, and Blood Chemistry Panel, and Urinalysis: Hematology includes hemoglobin, WBC, absolute neutrophils, absolute lymphocytes, and 
platelet count.  Blood chemistry includes AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, BUN (or 
urea), serum creatinine, uric acid, phosphorous (or phosphate), albumin, fasted glucose, and hemoglobin A1c.  Additional hematology/chemistries panels 
may be performed as clinically indicated.  Fasting glucose will be acquired at baseline C1D1, C1D15, and C2D1.  For all patients, including patients starting 
post-study anticancer therapy, 8 weeks after the completion of therapy, blood chemistry panel consisting of magnesium, total calcium, and potassium must 
be checked.  If abnormalities are observed, an ECG can be performed at the discretion of the investigator to check QTc.  Urinalysis will be conducted via 
urine dipstick for urine protein: if the result is positive, further diagnostic testing will be performed as clinically indicated.
m. Hemoglobin A1c: Hemoglobin A1c will be measured at C1D1, during the active treatment phase every 3 months from the date of randomization (ie, C4D1, 
C7D1, C10D1, etc.), and at the End of Treatment visit.
n.
Coagulation:  Coagulation analysis includes PT or INR and PTT/aPTT.
o.
12-Lead ECG: All ECGs should be obtained after a fast of at lease 1 hour.  For the purpose of this study, triplicate ECGs are defined as three consecutive 
ECGs performed approximately 2 minutes apart but within 10 minutes for all 3 ECGs at the protocol-specified timpoints to determine the mean QTc 
interval.
 
 
 
 
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r.
Archival Tumor Tissue Specimen: All patients will provide a FFPE archival tumor specimen, specifically a FFPE tissue block that contain sufficient tissue 
to generate at least 15 unstained slides, each with tissue sections that are 5 microns thick, or at least 15 unbaked glass slides, each containing an unstained 
5 micron FFPE tissue section if FFPE tissue block cannot be submitted.  If an archival tumor tissue sample is not available, a de novo tumor biopsy 
specimen must be obtained.  Specimens will be sent to the Sponsor-designated central laboratory.  Details for the handling of these specimens, including 
processing, storage, and shipment will be provided in the Study Manual.
s.
De Novo Tumor Specimens: Optional de novo tumor biopsy collection at screening, C1D15 or C2D15 (pre-dose, one time point only) and at the time of 
progression/End of Treatment is strongly encouraged; no more than 3 timepoints should be collected in total.  In all cases, these specimens will be provided 
in addition to the archival tumor tissue specimen that is required for enrollment.  Details for handling of these specimens including processing, storage, and 
shipment will be provided in the Study Manual. 
 
 
 
v.
Disease Assessments: Please refer to the Tumor Assessment Requirements Flowchart for details and timing of procedures.
w.
Drug Compliance: Palbociclib and placebo bottle(s), including any unused capsules, will be returned to the clinic for drug accountability.  Drug 
accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.
x.
AEs: For SAEs, the active reporting period begins from the time that the patient provides informed consent through and including 28 calendar days after the 
last administration of the investigational product.  Following the active safety reporting period, other SAEs of which the investigator becomes aware should 
be reported to Pfizer, unless the SAE is attributed by the investigator to complications of either the underlying malignancy or any subsequent anti-cancer 
therapy or to the patient’s participation in a subsequent clinical study.  AEs (serious and non-serious) should be recorded on the CRF from the time the 
patient has taken at least one dose of study treatment through last patient visit.
y.
Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 28 days after the last dose of study treatment. If a patient begins new therapy before the 28-day time period is complete, concomitant medication 
information will not be recorded (from the start date of the new therapy). This includes H1 antagonists pre-medication to alleviate cetuximab infusion 
reactions.
z.
EORTC-QLQ-C30 and EORTC-QLQ-H&N35 Assessments: Patients will complete questionnaires prior to any study or medical procedure on Day 1 of 
Cycles 1, 2 and 3 and then Day 1 of every other cycle thereafter starting with Cycle 5 (ie, Cycle 5, 7, 9, etc.), and at the End of Treatment visit. Four weeks 
after discontinuation of study treatment due to progressive disease, patients, including patients starting post-study anticancer therapy, will be completing the 
questionnaires at the Follow-up Visit.  All self-assessment questionnaires must be completed by the patients while in the clinic and cannot be taken home.  
Interviewer administration in clinic may be used under special circumstances, but family members are not permitted to assist with questionnaire 
administration.
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TUMOR ASSESSMENT REQUIREMENTS FLOWCHART
Screeninga
Treatment Periodb
End of Treatment Visitc
CT or MRI of Head and Neck (oral cavity, 
oropharynx, hypopharynx, larynx)d
Requirede
Required
Required
CT or MRI of Chest and Abdomen 
(including the liver)d
Requirede
Required
Required
CT or MRI of any other site of disease, as 
clinically indicated.
Requirede, f
Required for sites of disease 
identified at screening.
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere.
Photographs of all superficial lesions as 
applicableg
Required
Required for sites of disease 
identified at screening.
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere.
a.
Screening scans must occur within 4 weeks (ie, 28 days) prior to randomization unless otherwise specified. 
b.
Tumor assessment must be done during the treatment period, every 8 weeks (7 days) until radiographically and/or clinically (ie, for photographed or 
palpable lesions) documented PD as per RECIST v.1.1, initiation of new anticancer therapy, or discontinuation of patient from overall study participation 
(eg, death, patient's request, lost to follow up), whichever occurs first.  The schedule of assessments should be fixed according to the calendar, regardless 
of treatment delays/interruptions.  Imaging assessments are to be scheduled using the randomization date as the reference date for all time-points and are 
NOT to be scheduled based on the date of the previous imaging time-point.  Imaging assessment delay to conform to treatment delay is not permitted.  The 
same tumor assessment technique MUST be used throughout the study for a given lesion/patient. 
c.
Patients who have already demonstrated objective disease progression as per RECIST v.1.1 do not need to have scans repeated at the end of treatment visit 
or during the post-treatment follow-up.  For patients who do not have documented objective disease progression at time of study treatment discontinuation, 
tumor assessment will continue to be performed every 8 weeks (7 days) until radiographically and/or clinically confirmed objective disease progression, 
initiation of new anticancer therapy, or discontinuation of patient from overall study participation (eg, death, patient's request, lost to follow-up). 
d.
The CT scans, including brain CT scan if applicable, should be performed with contrast agents unless contraindicated for medical reasons.  If IV contrast is 
medically contraindicated, the imaging modality to be used to follow the disease (either CT without contrast or MRI) should be the modality which best 
evaluates the disease, and the choice should be determined by the investigator in conjunction with the local radiologist.  MRI of the abdomen can be 
substituted for CT if MRI adequately depicts the disease.  However, MRI of the chest should not be substituted for CT of chest even if IV contrast is 
contraindicated.  In such case CT will be performed without contrast.  If MRI is used to follow-up bone lesion(s) it must be performed a few days before 
any treatment that may affect bone-marrow cellularity (eg, G-CSF). 
e.
Radiographic assessments obtained per the patient’s standard of care prior to randomization into the study do not need to be repeated and are acceptable to 
use as baseline evaluations, if (1) obtained within 28 days before randomization, (2) they were performed using the method requirements outlined in 
RECIST v.1.1 (3) the same technique/modality can be used to follow identified lesions throughout the trial for a given patient, and (4) appropriate 
documentation indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes. 
f.
Baseline brain scans are required in patients with a history of metastatic brain disease.  Brain scans performed before the signing of informed consent as 
routine procedures (but within 6 weeks before randomization) do not need to be repeated and may be used as baseline assessments as long as (1) tests were 
performed using the method requirements outlined in RECIST v.1.1 (2) the same technique/modality can be used to follow identified lesions throughout 
the trial for a given patient (3) appropriate documentation indicating that these radiographic tumor assessments were performed as standard of care is 
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g.
Clinical assessment of superficial disease must be carried out on the same date as the imaging studies and will include photographs of all superficial 
metastatic lesions.  All lesion measurements must be recorded in the CRF.
Notes: 
- Radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression at the discretion of the investigator.  If progressive disease is 
confirmed per RECIST v.1.1, patients are expected to discontinue study therapy and begin the follow-up phase of the trial


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TABLE OF CONTENTS
PROTOCOL SUMMARY.......................................................................................................10
LIST OF TABLES...................................................................................................................28
APPENDICES .........................................................................................................................28
1. INTRODUCTION ...............................................................................................................29
1.1. Mechanism of Action/Indication.............................................................................29
1.2. Background and Rationale ......................................................................................30
1.2.1. Role of EGFR in SCCHN...........................................................................30
1.2.2. Deregulation of Cell Cycle Related Genes and Proteins in SCCHN..........30
1.2.3. Interaction of EGFR and CDK4/6 in SCCHN............................................30
1.2.4. Investigational Agents: Cetuximab.............................................................31
1.2.5. Investigational Agents: Palbociclib............................................................31
1.2.5.1. Pre-Clinical Data.......................................................................31
1.2.5.2. Clinical Data..............................................................................33
1.2.6. Dose Rationale for the Combination ..........................................................35
1.2.7. Study Rationale...........................................................................................35
1.2.8. Summary of Benefit Risk Assessment .......................................................36
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................36
2.1. Objectives................................................................................................................36
2.1.1. Primary Objective.......................................................................................36
2.1.2. Secondary Objectives .................................................................................36
2.2. Endpoints.................................................................................................................37
2.2.1. Primary Endpoint........................................................................................37
2.2.2. Secondary Endpoints ..................................................................................37
3. STUDY DESIGN.................................................................................................................38
4. PATIENT SELECTION......................................................................................................40
4.1. Inclusion Criteria.....................................................................................................40
4.2. Exclusion Criteria....................................................................................................42
4.3. Randomization Criteria ...........................................................................................44
4.4. Lifestyle Guidelines ................................................................................................44
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4.5. Sponsor’s Qualified Medical Personnel..................................................................45
5. STUDY TREATMENTS.....................................................................................................45
5.1. Allocation to Treatment ..........................................................................................45
5.1.1. Screen Failure .............................................................................................46
5.2. Breaking the Blind ..................................................................................................46
5.3. Patient Compliance .................................................................................................47
5.4. Drug Supplies..........................................................................................................47
5.4.1. Dosage Form(s) and Packaging..................................................................47
5.4.1.1. Palbociclib.................................................................................47
5.4.1.2. Placebo for Palbociclib..............................................................47
5.4.1.3. Cetuximab .................................................................................47
5.4.2. Preparation and Dispensing........................................................................47
5.4.2.1. Palbociclib/Placebo ...................................................................48
5.4.2.2. Cetuximab .................................................................................48
5.5. Administration.........................................................................................................48
5.5.1. Palbociclib/Placebo.....................................................................................48
5.5.2. Cetuximab...................................................................................................49
5.5.3. Recommended Dose Modifications............................................................50
5.5.3.1. Cetuximab Dose Modification Guidelines................................50
5.5.3.2. Palbociclib/Placebo Dose Modification Guidelines..................53
5.5.3.3. Palbociclib/Placebo Retreatment...............................................54
5.5.3.4. Palbociclib/Placebo Dose Reductions.......................................55
5.5.3.5. QTc Prolongation Management ................................................56
5.6. Drug Storage ...........................................................................................................57
5.7. Drug Accountability................................................................................................58
5.8. Concomitant Treatments .........................................................................................58
5.8.1. Prohibited Medications...............................................................................59
5.8.2. Medications Not Recommended.................................................................60
5.9. Concomitant Radiotherapy or Surgery....................................................................60
6. STUDY PROCEDURES .....................................................................................................60
6.1. Screening.................................................................................................................61
6.2. Active Treatment Phase ..........................................................................................61


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6.3. End of Treatment Visit............................................................................................62
6.4. Follow-up Visit .......................................................................................................62
6.5. Post-Study Patient Interview...................................................................................63
6.6. Patient Withdrawal..................................................................................................63
6.6.1. Active Treatment Phase Discontinuation ...................................................63
6.6.2. Study Discontinuation ................................................................................64
7. ASSESSMENTS..................................................................................................................65
7.1. Efficacy Assessments..............................................................................................65
7.1.1. Tumor Assessments....................................................................................65
7.1.1.1. Screening/Baseline Tumor Assessment ....................................66
7.1.1.2. Post-Baseline Tumor Assessments............................................66
7.1.2. Overall Survival..........................................................................................67
7.2. Pregnancy Testing...................................................................................................67
7.3. Safety Assessments .................................................................................................68
7.3.1. Laboratory Safety Assessments..................................................................68
7.3.2. Other Safety Assessments...........................................................................70
7.7. Patient Reported Outcomes.....................................................................................75
7.7.1. European Organisation for Research and Treatment of Cancer 
Quality of Life Instrument (EORTC QLQ-C30) (Appendix 3).......................76
7.7.2. European Organisation for Research and Treatment of Cancer Head 
and Neck Module 35 (EORTC QLQ-H&N35) (Appendix 4) .........................76
8. ADVERSE EVENT REPORTING......................................................................................76
8.1. Adverse Events........................................................................................................76
8.2. Reporting Period .....................................................................................................77
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8.3. Definition of an Adverse Event...............................................................................77
8.4. Medication Errors....................................................................................................78
8.5. Abnormal Test Findings..........................................................................................79
8.6. Serious Adverse Events...........................................................................................79
8.6.1. Protocol-Specified Serious Adverse Events...............................................80
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................80
8.7. Hospitalization ........................................................................................................81
8.8. Severity Assessment................................................................................................82
8.9. Causality Assessment..............................................................................................83
8.10. Exposure During Pregnancy..................................................................................83
8.11. Occupational Exposure .........................................................................................84
8.12. Withdrawal Due to Adverse Events (See Also Section on Patient 
Withdrawal)...............................................................................................................85
8.13. Eliciting Adverse Event Information ....................................................................85
8.14. Reporting Requirements........................................................................................85
8.14.1. Serious Adverse Event Reporting Requirements .....................................85
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................86
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................86
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................86
9.1. Sample Size Determination.....................................................................................86
9.2. Efficacy Analysis ....................................................................................................87
9.2.1. Analysis of Primary Endpoint ....................................................................87
9.2.2. Analysis of Secondary Endpoints...............................................................87
9.2.2.1. Progression-Free Survival.........................................................87
9.2.2.2. Objective Response...................................................................88
9.2.2.3. Duration of Response................................................................88
9.3.3. Patient-Reported Outcomes (PROs)...........................................................89
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9.4. Safety Analysis........................................................................................................90
9.4.1. Adverse Events...........................................................................................90
9.4.2. Laboratory Abnormalities...........................................................................90
9.4.3. Electrocardiogram (ECG)...........................................................................90
9.5. Interim Analysis ......................................................................................................91
9.6. Data Monitoring Committee ...................................................................................91
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................91
11. DATA HANDLING AND RECORD KEEPING .............................................................92
11.1. Case Report Forms/Electronic Data Record .........................................................92
11.2. Record Retention...................................................................................................92
12. ETHICS..............................................................................................................................93
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................93
12.2. Ethical Conduct of the Study ................................................................................93
12.3. Patient Information and Consent...........................................................................93
12.4. Patient Recruitment...............................................................................................94
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................94
13. DEFINITION OF END OF TRIAL...................................................................................94
13.1. End of Trial in a Member State.............................................................................94
13.2. End of Trial in All Other Participating Countries.................................................95
14. SPONSOR DISCONTINUATION CRITERIA ................................................................95
15. PUBLICATION OF STUDY RESULTS..........................................................................95
15.1. Communication of Results by Pfizer ....................................................................95
15.2. Publications by Investigators ................................................................................96
16. REFERENCES ..................................................................................................................97


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LIST OF TABLES
Table 1.
Palbociclib/Placebo Capsule Characteristics........................................................47
Table 2.
Cetuximab Available Dose Levels .......................................................................50
Table 3.
Cetuximab Dose Modifications in the Event of Acneiform Rash........................52
Table 4.
Palbociclib/Placebo Available Dose Levels.........................................................55
Table 5.
Palbociclib/Placebo Dose Modifications for Treatment Related Toxicities 
Requiring Treatment Interruption/Delay or Persisting Despite Optimal 
Medical Treatment................................................................................................56
Table 6.
Palbociclib/Placebo Dose Modifications in the Event of QTc Prolongation .......57
Table 7.
Summary of Biomarker Assessments...................................................................73
APPENDICES
Appendix 1. Adkins, D. Protocol # 201404139.....................................................................102
Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines...........................................................................................................103
Appendix 3. European Organisation for Research and Treatment of Cancer Quality of 
Life Instrument (EORTC-QLQ-C30).................................................................108
Appendix 4. European Organisation for Research and Treatment of Cancer Head and 
Neck Module 35 (EORTC-QLQ-H&N35).........................................................110
Appendix 5. Eastern Cooperative Oncology Group (ECOG) Performance Status ...............112
Appendix 6. List of Drugs Known to Predispose to Torsade de Pointes...............................113
Appendix 7. Bone Marrow Reserve in Adult ........................................................................114


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1. INTRODUCTION
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer.  
Globally, approximately 600,000 new cases occur yearly. In the United States, it is estimated 
that about 55,000 new cases of oral cavity, pharyngeal, and laryngeal cancers will occur in 
2014, which account for about 3% of new cancer cases. Data from a non-age-specific 
meta-analysis of 17,346 patients from 93 randomized trials presented oropharyngeal cancer 
as the most frequently observed (36%) SCCHN tumor type, followed by laryngeal and oral 
cavity cancers (21% each).1
An estimated 12,000 deaths from SCCHN will occur during 2014 in the United States (US).2
In the European Union (EU) an estimated 21,000 deaths from oral and hypopharyngeal 
cancers occurred each year between 2005 and 2009.3
Squamous cell carcinoma accounts for 90% of the head and neck tumors and the main risk 
factors include tobacco use, and alcohol use.4  Even though SCCHN is considered a 
predominantly male disease, several studies have reported a higher women proportion in the 
elderly SCCHN population, with a sex ratio close to 1. Tobacco and alcohol consumption 
were the major risk factors identified in 50% of the male population, whereas chronic oral 
trauma, leukoplakia and lichen planus were the predominant risk factors found in half of the 
female population.6  The oncogenic human papillomavirus (HPV) infection is a risk factor 
for oropharyngeal SCCHN.5 Patients with HPV infection tend to be younger than 
HPV-unrelated SCCHN patients.  HPV seems to have minor effect in the pathogenesis of 
SCCHN in the elderly population.  Advanced age itself is considered to be a risk factor for 
poor outcome. 
Local treatment of SCCHN often incorporates multimodality therapy and can be associated 
with significant functional sequelae.  Multimodality treatment including surgery and/or, 
radiation and/or chemotherapy is considered the best therapeutic options for patients with 
SCCHN.  Unfortunately, development of recurrent or even metastatic disease after therapy is 
common, and occurs in 40-60% of patients with locally advanced disease despite initially 
aggressive multimodal therapy. R/M disease is associated with poor outcomes and a median 
overall survival (OS) of 10-11 months in the first-line treatment setting, and about 6 months 
in the second-line treatment setting.  Chemoradiotherapy regimens have reached their upper 
limit of tolerability so that the investigation of new rational targets, based on the biology of 
the disease, is of major importance, thus highlighting the current need for more efficacious 
and better tolerated therapy.7
1.1. Mechanism of Action/Indication
Palbociclib is a highly selective, reversible oral inhibitor of cyclin-dependent kinases 4 and 6 
(CDK 4/6). The compound prevents cellular deoxyribonucleic acid (DNA) synthesis by 
prohibiting progression of the cell cycle from G1 into S phase.  Palbociclib is being 
developed in combination with cetuximab (Erbitux), an epidermal growth factor receptor 
(EGFR) antagonist, for the treatment of HPV-negative, cetuximab-naïve, R/M SCCHN after
failure of one platinum-based chemotherapy regimen.


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1.2. Background and Rationale
1.2.1. Role of EGFR in SCCHN
Epidermal growth factor receptor (EGFR) overexpression is found in approximately 90% of 
SCCHN cases8 and it is associated with decreased progression-free survival (PFS) and OS.9
The ErbB family of proteins contain four receptor tyrosine kinases, structurally related to 
EGFR, includes HER1 (EGFR, ErbB1), HER2 (EGFR, ErbB2), HER3 (ErbB3), and HER4 
(ErbB4). EGFR-directed drugs include antibodies that prevent ligand-binding and/or 
receptor dimerization (eg, cetuximab) and small molecule adenosine
triphosphate-competitive inhibitors of the intrinsic catalytic activity of ErbB receptors 
(eg, erlotinib and gefitinib). 
1.2.2. Deregulation of Cell Cycle Related Genes and Proteins in SCCHN
Important regulatory proteins involved in the cell cycle transition from G1 to the S-Phase are 
cyclin D1 (CCND1), p16INK4A (thereafter referred to as p16) and CDK4. Deregulation of 
aspects of the cell-cycle, including CDKs, have been shown to contribute to the development 
of cancer.10,11
CCND1, encoded by cyclin D1 is a well characterized member of the cyclin D family and is 
a positive regulator of the cell cycle (in complex with CDK4, see below) and is amplified in 
80% or more cases of HPV-negative SCCHN.12 Cyclin D1 has been recognized as a marker 
of poor prognosis.13,14,15,16,17,18 With platinums as important component of first line therapy 
of SCCHN it is noteworthy that Cyclin D1 overexpression in SCCHN was associated with 
cisplatin resistance in vitro, in vivo,19,20and clinically.21
CDK4 and CDK6 are two closely related kinases that are regulated by the cyclin D family 
members.22 In preclinical studies, increased levels of cyclin D and decreased levels of p16
(see below), have been associated with increased sensitivity to CDK 4 and 6 inhibition.23  
Preclinical studies suggest that inhibition of cyclin D-dependent kinase activity may prevent 
tumor growth.22
CDKN2A, which encodes p16, is considered a negative regulator of the cell cycle.  It is
inactivated in most cases of HPV-negative SCCHN by mutation, methylation in combination 
with chromosome loss or by homozygous deletion.24 Over-expression of cyclin D1, along 
with decreased expression of p16 and abrogation of p53 function, can cause cellular 
immortalization of oral keratinocytes.25 Thus, cyclin D1 overexpression in the context of 
decreased expression of p16 is likely to be an important driver of HPV-negative SCCHN. 
1.2.3. Interaction of EGFR and CDK4/6 in SCCHN
CCND1 is one of the many genes induced by intranuclear EGFR, linking cell cycle 
progression to EGFR stimulation.26  Data from SCCHN cell lines suggest an association 
between resistance to EGFR inhibitors and cyclin D1 amplification and/or overexpression.27


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1.2.4. Investigational Agents: Cetuximab
Cetuximab (Erbitux) is a chimeric monoclonal antibody directed against EGFR. In the US, 
EU, and Japan, cetuximab is approved in combination with radiation therapy for the 
treatment of locally advanced SCCHN and in combination with platinum-based
chemotherapy for the treatment of recurrent and/or metastatic SCCHN.  In the US it is also 
approved as a single agent for the treatment of patients with recurrent or metastatic SCCHN
for whom prior platinum-based chemotherapy has failed.
In a randomized Phase 3 trial conducted on 424 patients with locoregionally advanced 
(stage III or IV) SCCHN in which patients received either radiotherapy alone or radiation 
plus weekly cetuximab, cetuximab combined with radiotherapy improved median survival 
from 29.3 to 49.0 months (p-value = 0.03) and locoregional control from 14.9 to 24.4 months 
(p-value = 0.05).28,29
In randomized, open-label, multinational, Phase 3 clinical trials, cetuximab plus first-line 
platinum-based chemotherapy significantly improved OS (primary endpoint) compared with 
first-line platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN.7
This study demonstrated a significant benefit of cetuximab with an improvement in median 
OS from 7.4 months to 10.1 months (p-value = 0.04).
Three Phase 2 trials have investigated the role of cetuximab in patients with advanced 
SCCHN who had progressed on platinum-based chemotherapy.  In such trials, cetuximab 
administered as a single-agent in the second-line setting, was associated with response rates
between 10 and 13%, a median PFS of about 3 months, and a median OS of 6 months.30,31,32
Vermorken and colleagues conducted a pooled analysis of these trials.33 The analysis 
compared the outcome of these patients to that of patients who received a range of common 
second-line treatment approaches including best supportive care, palliative chemotherapy, 
radiotherapy and chemoradiotherapy in a retrospective study. The median OS for patients in 
the retrospective study was 3.4 months.
Cetuximab-related adverse events (AEs), which include skin rash, hypomagnesaemia and
infusion-related reactions, are mostly mild to moderate in severity and manageable. The 
most serious AEs associated with cetuximab are infusion reactions, cardiopulmonary arrest, 
dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, 
and pulmonary embolus. The current boxed warning includes infusion reactions and 
cardiopulmonary arrest.
1.2.5. Investigational Agents: Palbociclib
1.2.5.1. Pre-Clinical Data
1.2.5.1.1. Evidence of Palbociclib Single Agent Activity in SCCHN Tumor Models
Palbociclib (Molecular Weight: 447.53) is a highly selective inhibitor of CDK4/cyclinD1
kinase activity (IC50 = 11 nM; Ki= 2 nM).  Palbociclib has selectivity for CDK4/6, with little 
or no activity against a large panel of 274 other protein kinases including other Cdks and a 
wide variety of tyrosine and serine/threonine kinases.  CDK6, another enzyme that also 


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complexes with cyclin-D subunits, is also commonly expressed in mammalian cells and 
tumors. CDK6 is highly homologous to CDK4 and can perform the same function by
phosphorylating Rb, thus potentially creating a redundant mechanism to promote cell cycle
progression. Consequently, inhibition of both enzymes is necessary to ensure complete 
suppression of Rb phosphorylation and the greatest possible spectrum of antitumor activity.  
Results indicate that palbociclib inhibits CDK6 with equivalent potency to CDK4. 
Palbociclib showed anti-proliferative effects on Rb-positive cells in vitro and inhibition of 
tumor growth in several Rb-positive human breast and colon xenografts. In these models, 
palbociclib resulted in decreased Rb phosphorylation and decreased Ki-67 expression, but 
did not show activity in Rb-negative tumor xenografts.22  Additional information may be 
found in the Investigator’s Brochure (IB) for palbociclib. 
To assess the significance of CDK4/6 signaling in SCCHN, a breadth of efficacy studies 
were conducted across a panel of molecularly annotated cell lines and tumor explants.  In 
SCCHN cell lines palbociclib treatment produced growth arrest in the majority of models 
tested. Palbociclib treated cells showed reduced phosphorylation of Rb, inhibition of E2F 
signaling, and loss of CDK4/6 substrate FOXM1. Treated cell lines displayed inhibition of 
new DNA synthesis, measured through incorporation of EdU, and showed no signs of 
apoptosis when assessed through measurement of active caspases. To evaluate the efficacy 
of palbociclib in SCCHN models in vivo, tumor growth inhibition studies were run in a panel 
of three patient-derived xenografts.  Single agent palbociclib displayed equivalent or superior 
efficacy to single agent cetuximab treatment in these studies, with demonstration of 
>90% inhibition in one model and partial inhibition (>60% TGI) in one model (unpublished 
data, data on file at Pfizer).
1.2.5.1.2. Evidence for Additive/Synergistic Activity for the Combination of Palbociclib
and Cetuximab
Combinatorial efficacy was observed following treatment with palbociclib and inhibitors of 
the EGFR pathway, including cetuximab, in preclinical models.  In a panel of 24 SCCHN 
cell lines the palbociclib combination with cetuximab produced synergistic growth inhibition 
in 50% of models. The combination of palbociclib and cetuximab in a subset of these cell 
lines demonstrated increased inhibition of pRb and downstream E2F signaling, leading to 
greater inhibition of new DNA synthesis and increased hallmarks of cellular senescence than 
with each agent alone. In vivo studies in patient-derived xenografts demonstrated the ability 
of either single agent to produce >90% tumor growth inhibition in distinct models, and in a 
model that failed to show significant response to either single agent, the combination of 
palbociclib and cetuximab yielded synergistic tumor growth inhibition. 
1.2.5.1.3. Overview of Nonclinical Safety Data
The nonclinical safety profile of palbociclib has been well characterized through the conduct 
of single- and repeat-dose toxicity studies up to 39 weeks in duration, and safety 
pharmacology, genetic toxicity, reproductive and developmental toxicity, and phototoxicity 
studies. 


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Consistent with the pharmacologic activity of palbociclib (cell cycle inhibition, 
CDK4/6 inhibition), the primary target organ findings included hematolymphopoietic 
(decreased cellularity of bone marrow and lymphoid organs) and male reproductive organ 
(seminiferous tubule degeneration, and secondary effects on the epididymis, prostate, and 
seminal vesicle) effects in rats and dogs, and altered glucose metabolism that was 
accompanied by effects on the pancreas and secondary changes in the eye, teeth, kidney, and 
adipose tissue in rats only, and effects on bone in rats only that were observed following 
single and/or repeat dosing at clinically relevant exposures.  Altered glucose metabolism 
(hyperglycemia/glucosuria) correlated with pancreatic islet cell vacuolation that was 
determined to reflect a loss of beta cells with corresponding decreases in insulin and 
C-peptide.  The reversibility of the effects on glucose homeostasis, pancreas, eye, kidney, 
and bone was not established following a 12-week non-dosing period; whereas partial to full 
reversal of effects on the hemato-lymphopoietic and male reproductive systems, teeth, and 
adipose tissue were observed.
Additionally, a potential for QTc prolongation and hemodynamic effects were identified 
from safety pharmacology studies, and developmental toxicity was identified from 
embryo-fetal development studies in the rat and rabbit.
Though gastrointestinal effects would be anticipated from a cell cycle inhibitor and while 
effects were observed in rats and dogs following single- and repeat-dose studies up to 
3 weeks in duration (emesis, fecal changes, and microscopic changes in stomach and
intestines), the effects were of limited severity at clinically relevant doses.  Gastrointestinal 
effects were not prominent in longer duration studies, limited to effects on the glandular 
stomach and rodent-specific effects on the non-glandular stomach in rats following 27 weeks 
of intermittent dosing that did not reverse during a 12-week non-dosing period.  Additional
palbociclib-related findings considered non-adverse at tolerated doses based on limited 
severity and/or absence of degenerative changes included cellular vacuolation in multiple 
tissues that was morphologically consistent with phospholipidosis; hepatic (increases in liver 
enzymes, hepatocellular hypertrophy/increased vacuolation), renal (increased chronic 
progressive neuropathy), adrenal (cortical cell hypertrophy), and respiratory (clinical signs, 
tracheal epithelial cell atrophy) effects; and prolonged coagulation times.  Reversibility 
(partial or full) was established for these additional toxicities.  Finally, palbociclib was 
determined to be an aneugen, for which a no effect exposure was identified.  Additional 
information may be found in the IB for palbociclib.
1.2.5.2. Clinical Data
Two Phase 1 trials evaluated single agent administration of palbociclib to patients with 
Rb-positive cancers.34,35 One of these trials determined that the dose-limiting toxicity (DLT) 
was neutropenia and the maximum tolerated dose (MTD) was 125 mg once daily when 
administered for 21 of 28 days (3/1 schedule). The most common non-hematologic AEs 
included fatigue, nausea, and diarrhea.  The mean half-life of palbociclib was 26.9 hours.  
Patients were selected for Rb-positive cancers, based on immunohistochemistry (IHC) stain, 
defined as positive if staining intensity was 1+ or greater above background.  Stable disease 
for 4 cycles (16 weeks) occurred in 27% of evaluable patients and in a number of tumor 
types (liposarcoma, testicular, renal, ovarian, breast, appendiceal, peritoneal, melanoma, 


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thymoma and lung).  Another Phase I trial of palbociclib using an alternative dosing plan 
(21 day cycles; 2/1 schedule) observed a similar likelihood of disease control in a variety of 
tumor types.34 These studies demonstrate that palbociclib has substantial activity in 
Rb-positive tumors. 
A randomized Phase 2 trial initiated to determine the overall safety and efficacy of 
palbociclib (125 mg) and letrozole (2.5 mg) versus letrozole in post-menopausal women with 
ER+ HER2-negative advanced breast cancer.36  The overall objective response rate (ORR)
was 45% for those women who received palbociclib plus letrozole versus 31% for those who 
received letrozole (statistically significant).  Importantly, the median PFS was significantly 
different (26.2 versus 7.5 months) favoring the combination arm.
The most common adverse drug reactions of any grade reported in patients in the palbociclib
plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, 
nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, 
asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse 
drug reaction in patients receiving palbociclib plus letrozole was diarrhea (2.4%).
Overall, neutropenia of any grade was reported in 62 (74.7%) patients in the combination 
arm, with Grade 3 neutropenia being reported in 40 (48.2%) patients, and Grade 4 
neutropenia being reported in 5 (6.0%) patients.
In the combination arm, 56.6% of patients had a maximum grade of Grade 3 neutropenia and 
4.8% of patients had a maximum grade of Grade 4 neutropenia based on laboratory data. 
The median time to first episode of neutropenia was 15 days for any grade, Grade 2, and 
Grade 4 neutropenia, and 28 days for Grade 3 neutropenia in the palbociclib plus letrozole 
arm.Median duration of Grade 3 or 4 neutropenia was 7 days. Most episodes of Grade 3 
neutropenia were managed by dose reduction and/or dose delay or temporary discontinuation 
and did not require permanent discontinuation of study treatment or addition of supportive 
therapy.
Palbociclib, in combination with anti-hormonal treatment, is currently being tested in large 
Phase 3 studies, in patients with advanced ER+ HER2-negative breast cancer.
Palbociclib has also demonstrated activity in a broad range of other solid tumors and 
hematological malignancies.  In relapsed mantle cell lymphoma selected for cyclin D1 
overexpression,37 the objective response (complete response [CR] or partial response [PR]) 
rate was 18% and the stable disease (SD) rate was 41%.  Significant reductions in 
phospho-Rb (89%) and Ki-67 (74%) occurred in paired biopsy samples after treatment with 
palbociclib. 
In a study in 29 patients with well-differentiated and dedifferentiated liposarcoma,
Dickson et al reported a 66% (90% CI, 51% to 100%) PFS rate at 12 weeks. The median 
PFS was 18 weeks, and there was one partial response. Grade 3 to 4 events included anemia, 
thrombocytopenia, neutropenia, and febrile neutropenia in one patient.38


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In an ongoing Phase 1 clinical trial of escalating doses of palbociclib added to fixed dose 
cetuximab in patients with SCCHN, one partial tumor response was observed in a patient 
with SCCHN resistant to cetuximab and cisplatin. Disease control (PR or SD) occurred in 
6 of the 7 evaluable patients. Of the 6 patients with cetuximab-resistant SCCHN, 
5 experienced disease control with combined palbociclib + cetuximab treatment. Of the 
4 patients with cisplatin-resistant SCCHN, 3 experienced disease control with palbociclib + 
cetuximab. These clinical data support significant potential efficacy of palbociclib in 
SCCHN (Appendix 1).  Further data analyses, including PK, safety, and efficacy analysis, are 
in progress for this study. Additional information may be found in the IB for palbociclib.
1.2.6. Dose Rationale for the Combination
In the aforementioned ongoing Phase 1 dose escalation study, palbociclib was administered
at doses of 100 and 125 mg QD for 21 out of 28 days (3/1 schedule).  Cetuximab was 
administered at the initial dose of 400 mg/m2 as a 120-minute IV infusion, followed by 
250 mg/m2 weekly dose, infused over 60 minutes. The combination was well tolerated 
without any DLTs observed at either dose level. Uncomplicated neutropenia was the most 
frequent AE. Based on this study, the recommended Phase 2 dose (RP2D) was determined to 
be 125 mg of palbociclib administered on the 3/1 schedule in combination with the standard 
dose for cetuximab.
Complete information for palbociclib may be found in the Single Reference Safety 
Document (SRSD), which for this study is the IB.  The SRSD for the active comparator 
agent, cetuximab (Erbitux), is the most recent version of the Summary of Product 
Characteristics (SPC).39
1.2.7. Study Rationale
HPV-negative, R/M, SCCHN represents a disease with a dismal prognosis.  Although the 
EGFR inhibitor cetuximab is an important recent addition to the treatment options for the 
second-line treatment of SCCHN, it has resulted in only modest improvements in clinical 
outcomes, and no standard of care exists.  Therefore, newer treatments or treatment regimens 
with novel mechanisms of action are desperately needed. 
Overexpression of cyclin D1 and inactivation of p16 occur in the vast majority of cases of 
HPV-negative SCCHN, but not in HPV-related SCCHN, in which both loss of Rb and high 
p16 expression levels are common.  Genomic characterization of oral HPV-negative SCCHN 
identified amplification of CCND1 (cyclin D1) and/or loss of CDKN2A (p16) in 94% of 
tumors, supporting that cell cycle alterations are a nearly universal feature in this patient 
population,32 and that a drug targeting cell cycle such as palbociclib may be appropriate to 
test in this disease setting.
A breadth of preclinical in vitro and in vivo efficacy studies were conducted in which 
palbociclib displayed equivalent or superior efficacy to single agent cetuximab treatment and 
combination treatment with the two agents increased efficacy and/or the DR.


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Based on the evidence presented, the proposed Phase 2 study provides the opportunity to test
the hypothesis that the addition of palbociclib to cetuximab will improve outcomes in 
patients with recurrent or metastatic SCCHN after failue of one platinum-containing regimen.
1.2.8. Summary of Benefit Risk Assessment
Current second-line treatments for HPV-negative, R/M, SCCHN have minimal effectiveness 
and are undesirably toxic.  The result is OS in this setting is very short; therefore, there is a 
high unmet medical need for new and improved treatment options.
The potential benefits of the present study are based on sound preclinical and preliminary 
clinical evidence that inhibition of the cyclin D1/CDK4 axis by palbociclib in combination 
with EGFR inhibition by cetuximab can be an effective treatment for patients with incurable, 
cetuximab-naïve, HPV-negative SCCHN. It can be expected that patients will benefit from 
prolonged survival, PFS, and other health-related outcomes, such as delayed deterioration or 
improvement of global health status, pain and swallowing capabilities. 
Potential risks associated with palbociclib include non-cumulative, reversible, uncomplicated 
neutropenia (about 50% Grade 3) managed by dose reduction and/or dose delay or temporary 
discontinuation without the requirement of permanent discontinuation of treatment or 
addition of supportive therapy. Other risks associated include leukopenia, fatigue, anemia, 
upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, 
decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. Risks 
associated with cetuximab include infusion reactions, dermatologic toxicity, cardiac arrest,
and hypomagnesemia. The overall toxicity profiles of palbociclib and cetuximab do not 
overlap.
Therefore, the potential benefits outweigh the potential risks, supporting an overall favorable 
benefit/risk assessment in the treatment of patients with incurable, cetuximab-naïve, 
HPV-negative R/M SCCHN after failure of one platinum-containing regimen.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective

To demonstrate that the combination of palbociclib with cetuximab is superior to 
cetuximab in prolonging OS in HPV-negative, cetuximab-naïve patients with R/M 
SCCHN in whom one prior platinum-containing chemotherapy has failed.
2.1.2. Secondary Objectives

To compare secondary measure of efficacy between the treatment arms;

To compare safety and tolerability between the treatment arms; 

To compare Patient-Reported Outcome (PRO) measures between the treatment arms;


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
To characterize the correlations between baseline biomarker (eg, p16, Rb) expression 
in tumor tissue and clinical efficacy in both treatment arms;

To characterize steady state trough concentrations for palbociclib, and trough and 
maximum concentrations for cetuximib in patients with R/M SCCHN.
 
 
 
 
2.2. Endpoints
2.2.1. Primary Endpoint

Overall Survival.
2.2.2. Secondary Endpoints

PFS, Objective Response (OR), and DR, according to Response Evaluation Criteria in 
Solid Tumours (RECIST verson [v.]1.1, see Appendix 2), as assessed by investigator; 

Type, incidence, severity (as graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events [NCI CTCAE] v. 4.03), seriousness and 
relationship to study medications of AEs and any laboratory abnormalities;

PRO endpoints: European Organisation for Research and Treatment of Cancer 
Quality of Life Instrument (EORTC-QLQ-C30, see Appendix 3); European 
Organisation for Research and Treatment of Cancer Head and Neck Module 35 
(EORTC-QLQ-H&N35, see Appendix 4);

Tumor tissue biomarkers by IHC (p16 and Rb);

Trough concentrations at steady state for palbociclib; trough and maximum 
concentrations for cetuximib.
CCI


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3. STUDY DESIGN
This is an international, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group Phase 2 study comparing the efficacy and safety of palbociclib in combination 
with cetuximab versus cetuximab in HPV-negative, cetuximab-naïve patients with R/M 
SCCHN after failure of one platinum-containing regimen.  Approximately 120 patients will 
be randomized 1:1 between the investigational arm (Arm A: palbociclib plus cetuximab) and 
the comparator arm (Arm B: placebo plus cetuximab).  Crossover between treatment arms 
will be prohibited.
Patients will be stratified by Eastern Cooperative Oncology Group (ECOG, see Appendix 5) 
performance status (0 vs 1), and by prior use of immunotherapy (yes vs no).
Patients randomized to Arm A (investigational arm) will receive:

Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed 
by 7 days off treatment in a 28-day cycle; 
in combination with

Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion 
followed by 250 mg/m2 weekly infused over 60 minutes.
Patients randomized to Arm B (comparator arm) will receive: 

Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in 
a 28-day cycle; 
in combination with

Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 
250 mg/m2 weekly infused over 60 minutes.
Patients will continue to receive their assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first. 
CCI


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The importance of timely and complete disease assessments in this study cannot be 
overstated.  Disease assessments will be performed every 8 weeks (7 days) from the date of 
randomization.  Each assessment will be performed as scheduled according to the calendar 
regardless of any dosing delay to prevent the introduction of bias into the assessment of 
efficacy.  Failure to perform any of the required disease assessments will result in the 
inability to determine disease status for that time point.  Tumor assessments will be 
performed until radiographically and/or clinically (ie, for photographed or palpable lesions) 
documented PD as per RECIST v.1.1, initiation of new anticancer therapy, or discontinuation 
of patient from overall study participation (eg, death, patient's request, lost to follow-up), 
whichever occurs first.  Off schedule or incomplete disease assessments have the potential to 
weaken the conclusion of this clinical trial and must be avoided wherever possible.
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented PD as per RECIST
v.1.1 will continue to have tumor assessment performed during the follow-up visits every 
8 weeks (7 days) until RECIST-defined disease progression, initiation of new anticancer 
therapy or discontinuation of patient from overall study participation (eg, death, patient's 
request, lost to follow-up), whichever occurs first. 
Patients discontinuing the active treatment phase will enter a follow-up period during which 
survival and new anti-cancer therapy information will be collected every 2 months from the 
last dose of investigational product.  The follow-up period will conclude at the time of the 
final OS analysis.  Crossover will not be allowed in the trial.
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as the primary data source.
Patients will undergo study-related safety, efficacy, and PK assessments as outlined in the
Schedule of Activities section.
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers assessed in tumor tissue and blood obtained prior to 
treatment for their potential predictive value in identifying patients who may benefit from 
treatment with cetuximab in combination with palbociclib or placebo.  Blood and tumor 
(optional) biomarkers also assessed on-treatment provide an opportunity to investigate 
pharmacodynamics effects, and tumor specimen (optional) and blood collected upon disease 
progression (end of treatment) will be analyzed to investigate potential mechanisms of 
resistance to treatment.
In addition, blood samples will be collected from all patients in Cycles 1 and 2 to assess 
steady-state trough concentrations of palbociclib and pre- and post-infusion concentrations of 
cetuximab to provide an opportunity to conduct an exploratory exposure/response analysis 
for safety and efficacy findings as well as correlative analyses between drug exposure and 
biomarker changes from baseline.


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Examining and measuring the patient’s subjective experience in this study will be 
accomplished using health-related quality of life questionnaires. These assessments provide 
the means to validly and reliably quantify subjective information, which is provided by the 
study patients in response to specific questions from validated instruments.  Observations 
will be documented at specified timepoints throughout the study, plus 1 observation after 
treatment discontinuation (to measure the impact of progressive disease on the patient’s 
quality of life).
An independent third party E-DMC will monitor the the efficacy and safety of patients in the 
study according to the Charter. The E-DMC will make recommendation as to whether or not 
the trial should continue based on ongoing reviews of safety data.  In addition, the E-DMC 
will also evaluate interim efficacy data and make a recommendation regarding study 
continuation based on observed results of the study.  The recommendations made by the 
E-DMC to alter the conduct of the study will be forwarded to Pfizer for final decision. 
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, 
oropharynx, hypopharynx or larynx, not amenable for salvage surgery or radiotherapy.
2. Measuarable disease as defined per RECIST v. 1.1. Tumor lesions previously irradiated 
or subjected to other locoregional therapy will only be deemed measureable if disease 
progression at the treated site after completion of therapy is clearly documented.
3. HPV- negative SCCHN tumor as determined per institutional standard (eg, p16 IHC; 
multiplex nucleic acid sequence based amplification [NASBA] or other polymerase chain 
reaction [PCR]-based assays).
4. Documented progressive disease according to RECIST v1.1 (Appendix 2) following 
receipt of at least 2 cycles of one platinum-containing chemotherapy regimen
administered for R/M disease (min. 50 mg/m2 for cisplatin, minimum area under the 
curve [AUC] >4 for carboplatin).


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5. Availability of a tumor tissue specimen (ie, archived formalin fixed paraffin embedded 
tissue [block preferred, or 15 unstained slides]), which will be used for centralized, 
retrospective biomarker analysis.  If archived tumor tissue is not available, then a de novo
biopsy will be required for patient participation.
6. ECOG performance status (PS) 0 or 1 (Appendix 5).
7. Adequate organ and marrow function defined as follows: 

Leukocytes >3,000/mm3 (3.0 x 109 /L);

Absolute Neutrophil count (ANC) 1,200/mm3 (1.2 x 109 /L); 

Platelets 75,000/mm3 (75 x 109 /L); 

Hemoglobin (Hb) 9 g/dL (90 g/L); 

Serum creatinine 1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance 40 mL/min as calculated using the method standard for the institution; 

Total serum bilirubin 1.5 x ULN (3.0 x ULN if Gilbert’s disease);

Asparate aminotransferase (AST) and/or alanine aminotransferase (ALT) 2 x ULN 
(5.0 x ULN if liver metastases present); 

Alkaline phosphatase 2.5 x ULN (5.0 x ULN if bone or liver metastases present). 
8. Male and female patients of childbearing potential and at risk for pregnancy must agree 
to use two highly effective methods of contraception throughout the study and for 
6 months after the last dose of cetuximab.
Female subjects who are not of childbearing potential (ie, meet at least 1 of the following 
criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed by having a serum follicle stimulating hormone
(FSH) level within the laboratory’s reference range for postmenopausal women.
9. Age 18 years (or 20 years as applicable by local country regulations).
10. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects 
of the study.


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11. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the study:
1. Prior nasopharyngeal cancer, salivary gland or sinus tumors.
2. More than one chemotherapeutic regimen given for R/M disease.  Prior treatment with 
immunotherapy is allowed.
3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, 
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth.  Patients with a history of CNS metastases or 
cord compression are eligible if they have been definitively treated with local therapy 
(eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and 
steroids for at least 4 weeks before randomization.
4. Progressive disease within 3 months after completion of curatively intended treatment for 
locoregionally advanced SCCHN. 
5. Inability to swallow capsules.
6. Prior use of cetuximab in the R/M disease treatment setting.
7. Prior treatment with any CDK4/6 or EGFR inhibitor (except cetuximab during curative 
radiotherapy).
8. Patients treated within the last 7 days prior to randomization with:

Food or drugs that are known to be strong CYP (cytochrome P-450) 3A4 inhibitors 
(ie, 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 or 
grapefruit juice);

Drugs that are known to be strong CYP3A4 inducers (ie, carbamazepine, felbamate, 
nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and 
St. John’s wort);

Drugs that are known to prolong the QT interval (Appendix 6).
9. Major surgery, chemotherapy, radiotherapy, any investigational agents, or other 
anti-cancer therapy within 2 weeks before randomization.  Patients who received prior 
radiotherapy to 25% of bone marrow (Appendix 7) are not eligible independent of when 
it was received.


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10. Diagnosis of any other malignancy within 3 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
cervix.
11. QTc >480 msec (based on the mean value of the triplicate electrocardiograms (ECGs), 
family or personal history of long or short QT syndrome, Brugada syndrome or known 
history of QTc prolongation, or Torsade de Pointes.
12. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging 
drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).
13. Any of the following within 6 months of randomization: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE 
version 4.03 Grade 2, atrial fibrillation of any grade, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure, cerebrovascular accident including transient 
ischemic attack, or symptomatic pulmonary embolism.
14. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any 
upper gastrointestinal surgery including gastric resection that could impair drug 
absorption.
15. Known human immunodeficiency virus infection.
16. Other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior, or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into this 
study.
17. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cetuximab.
18. Pregnant female subjects; breastfeeding female subjects; male and female subjects of 
childbearing potential who are unwilling or unable to use two highly effective methods of 
contraception as outlined in this protocol for the duration of the study and for 6 months
after the last dose of cetuximab.
19. Patients who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of the 
study.
20. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks before the current study begins and/or during study participation.


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4.3. Randomization Criteria
Patients will be randomized into the study provided they have satisfied all patient selection 
criteria. 
The investigators or their pre-specified designee will randomize eligible patients by 
interactive randomization technology (IRT) as described in the Study Reference Manual. 
At the time of randomization, information about patient demographics and stratification 
factors (ie, ECOG PS [0 vs 1] and prior use of immunotherapy [yes vs no]) will be requested. 
The central computerized system will provide the randomization number and treatment 
assignment.
4.4. Lifestyle Guidelines
In this study, all male and female patients of childbearing potential, as defined in Inclusion 
Criterion 8, must agree to use 2 methods of highly effective contraception throughout the 
study and continue for 6 months after the last dose of cetuximab.  The investigator or his/her 
designee, in consultation with the patient, will confirm the patient has selected 2 appropriate 
methods of contraception for the individual patient (and his female partner as warranted)
from the list of permitted contraception methods (see below) and confirm that the patient has 
been instructed in their consistent and correct use.  Patients need to affirm that they meet at 
least 2 of the selected methods of contraception.  The investigator or his/her designee will 
discuss with the patient the need to use highly effective contraception consistently and 
correctly according to the Schedule of Activities and document such conversation in the 
patient’s chart.  In addition, the investigator or his/her designee will instruct the patient to 
call immediately if a selected contraception method is discontinued or if pregnancy is known 
or suspected. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected, or implanted hormonal methods of 
contraception are allowed provided the patient plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.


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5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for 6 months after the last dose
of cetuximab.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list, located in the coordinator’s manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a help desk in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The help desk number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should only be 
used in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace,
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The help desk 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
If the patient is found to be eligible for the study, he/she should be randomized using a 
centralized internet/telephone registration system no more than 4 calendar days before 
administration of the first dose of investigational product. 
Allocation of patients to treatment groups will proceed through the use of an Interactive 
Reponse Technology (IRT) system (Interactive Web Response (IWR)/Interactive Voice 
Response (IVR) System).  The site personnel (study coordinator or specified designee) will 
be required to enter or select information including, but not limited to, the user’s 
identification (ID) and password, protocol number, the patient number and date of birth of 
the patient.  The site personnel will then be provided with a randomization number and 
dispensable unit (DU) or container number when drug is being supplied via the IRT.  The 
IRT system will provide a confirmation report containing the patient number and DU or 
container number assigned.  The confirmation report must be stored in the site’s files.


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There is a 24 hour a day, 365 days a year IRT helpdesk available for any questions or issues.  
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT.
Note: The IRT is the source of the patient number.  The IRT system will provide the patient 
number at the end of the first IRT patient transaction.
Eligible patients will be randomly assigned in a 1:1 ratio to either Arm A (investigational
arm: palbociclib plus cetuximab) or Arm B (comparator arm: placebo plus cetuximab) 
stratified according to ECOG PS and prior use of immunothrapy (see Section 4.3).
Clinical sites must complete the screening CRFs for all registered and randomized patients, 
even if the patient is not subsequently treated in this study. 
At the time of registration, the clinical site staff must provide site and patient identifiers and 
demographic information.  The IRT will assign a unique patient identification number.  The 
IRT system will also be used to assign study medication.
If a patient does not receive the correct study treatment for their allocated treatment arm, the 
reason must be clearly documented in CRF.  The patient will remain on study, baseline data 
will be collected and follow up will continue as described in the Schedule of Activities table.
5.1.1. Screen Failure
Patients who completed the informed consent process but do NOT meet all eligibility criteria 
and therefore are NOT randomized to either treatment arm will be considered as screen 
failures. Please see Section 4.1 and Section 4.2 for detailed inclusion and exclusion criteria.
Clinical sites must provide for all screen failures the following information using the
appropriate CRFs: screening number, demographic data as well as the final patient summary 
including the reason for screening failure.
5.2. Breaking the Blind
At the initiation of the trial, the trial site will be instructed on the method for breaking the 
blind.  The method will be either a manual or electronic process.  Blinding codes should only 
be broken in emergency situations for reason of patient safety.  Blinding codes may also be 
broken after a patient discontinues treatment due to disease progression, as determined by the 
treating investigator using RECIST v.1.1, but only if deemed essential to allow the 
investigator to select the patient's next treatment regimen and after discussion and agreement 
with the sponsor.  Code should not be broken in the absence of emergency situations or 
progressive disease as per RECIST v.1.1 (eg, in case of clinical deterioration, increase in 
tumor markers or any other evidence suggestive of disease progression but in the absence of 
RECIST-defined disease progression).  When the blinding code is broken, the date and 
reason for unblinding must be fully documented in source documents and entered on the 
CRF.  However, every effort should be made by the site staff to ensure that the treatment arm 
in which the unblinded patient is assigned is not communicated to any sponsor personnel or 
designee involved in the conduct of the trial.


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5.3. Patient Compliance
Patients will be required to return all bottles of palbociclib/placebo as well as the completed 
patient diary at the beginning of each cycle for drug accountability.  Drug accountability will 
be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle.  The 
number of remaining capsules will be documented and recorded. 
All doses of cetuximab will be administered by study staff, at the investigational site.
5.4. Drug Supplies
The investigational drugs used in the course of this trial are palbociclib/placebo. 
5.4.1. Dosage Form(s) and Packaging
5.4.1.1. Palbociclib
Palbociclib will be supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of 
palbociclib free base.  The sponsor 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, as shown in Table 1. Labeling will 
occur according to local regulatory requirements.
Table 1.
Palbociclib/Placebo Capsule Characteristics
Strength
Capsule color
75 mg
Sunset Yellow
100 mg 
Caramel/Sunset Yellow
125 mg
Caramel
5.4.1.2. Placebo for Palbociclib
Placebo for palbociclib will be indistinguishable from the palbociclib capsules and will be 
supplied as capsules matching in size and color the various palbociclib formulations 
(Table 1).  The sponsor will supply placebo to sites in HDPE bottles. Labeling will occur 
according to local regulatory requirements.
5.4.1.3. Cetuximab
Cetuximab is commercially available in multiple presentations. Presentations containing 
100 mg of cetuximab per vial will be used in this study.  Commercial supplies of cetuximab 
will be centrally sourced and provided to sites.  Detailed information about cetuximab 
formulation can be found in the locally approved package insert for Erbitux®.
5.4.2. Preparation and Dispensing
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
palbociclib/placebo, and cetuximab.


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See the locally approved package insert for instructions in how to prepare cetuximab for 
administration. Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance.
5.4.2.1. Palbociclib/Placebo
The patient number should be recorded on the bottle label in the spaces provided by site 
personnel at the time of assignment to patient.  Site personnel must ensure that patients 
clearly understand the directions for self-medication.  Patients should be given a sufficient 
supply to last until their next study visit.  Unused drug and/or empty bottles should be 
returned to the site at the next study visit.  Returned, unused medication MUST NOT be 
re-dispensed to the patient. 
Palbociclib/placebo 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 one capsule strength will be dispensed to the patient at each dispensing visit.  In the 
event of dose modification, request should be made of the patient to return all previously 
dispensed medication to the clinic and new capsules will be dispensed.
5.4.2.2. Cetuximab
Cetuximab is commercially available in multiple presentations.  Presentations containing 
100 mg of cetuximab per vial will be used in this study.  Commercial supplies of cetuximab 
will be centrally sourced and provided to sites.
Do not shake or dilute the medication, and discard unused portion after 8 hours at controlled 
room temperature (20to 25C; 68F to 77F) or after 12 hours at 2to 8C (36F to 46F).  
Detailed information about cetuximab preparation and dispensing can be found in the locally 
approved package insert for Erbitux.
5.5. Administration
5.5.1. Palbociclib/Placebo
Patients should be instructed to swallow one palbociclib/placebo capsule daily, whole, and 
not to chew them prior to swallowing.  No capsule should be ingested if it is broken, cracked, 
or otherwise not intact. Patients should contact site personnel if capsules are not intact for 
replacement capsules. Patients should be encouraged to take their dose at approximately the 
same time each day.  Patients should be instructed to record daily administration of the study 
drugs in a patient diary.


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Patients must be instructed to withhold their daily dose of palbociclib/placebo on 
pharmacokinetic sampling days until the pre-dose pharmacokinetic sample and safety 
assessments (ie, hematology, blood chemistry and ECGs) have been completed.  On days the 
patient is in the clinic, palbociclib/placebo will be taken when instructed by the investigator.
Patients should take palbociclib/placebo with food. 
One palbociclib/placebo capsule will be administered once a day, orally, for 21 days
followed by 7 days off treatment in 28-day cycles.
Patients who miss a day’s dose entirely must be instructed NOT to “make it up” the next day.
Patients who vomit any time after taking a dose must be instructed NOT to “make it up,” and 
to resume treatment the next day as prescribed. 
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the next 
day’s dose.  Also refer to Section 8.4 for further details on medication errors and overdose.
Patients experiencing investigational product related toxicity may have their dose modified 
according to Section 5.5.3.
Patients who become unable to swallow palbociclib/placebo capsules will discontinue study 
treatment.
5.5.2. Cetuximab
All patients will be premedicated with an H1 antagonist (eg, 50 mg of diphenhydramine) 
intravenously 30-60 minutes prior to the first dose. All patients will also be premedicated 
with a corticosteroid at least 1 hour prior to administration of the first dose of cetuximab.
Premedication should be administered for subsequent cetuximab doses based upon clinical
judgment and presence/severity of prior infusion reactions. Note: Systemic dexamethasone 
use is not recommended due to possible drug-drug interactions.
Administer 400 mg/m2 (initial dose) as a 120-minute IV infusion with the maximum infusion 
rate of 10 mg/min.  Subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 
60 minutes with the maximum infusion rate of 10 mg/min.  Detailed information can be 
found in the locally approved package insert for Erbitux.  Note: do not administer 
cetuximab as an IV push or bolus.  Do not exceed an infusion rate of 10 mg/min. Body 
surface area will be calculated per institutional standard.  Patients need to be closely 
monitored for all vital signs for the two hour duration of the initial cetuximab infusion, and 
for the one hour duration of subsequent infusions, plus an additional one hour after 
completion of all infusions.


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5.5.3. Recommended Dose Modifications
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 study drugs 
(palbociclib/placebo or cetuximab) may need to be adjusted as described in the following 
sections.  Depending on the nature of the toxicity observed, dosing adjustment may be 
required for just one or both study drugs in the combination. 
In the event of significant treatment-related toxicity, palbociclib/placebo and/or cetuximab
dosing may be interrupted or delayed and/or reduced as described below.  In the event of 
multiple toxicities, dose modification should be based on the worst toxicity observed.  
Patients are to be instructed to notify Investigators at the first occurrence of any adverse sign 
or symptom.
Dose modifications may occur in three ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle;

Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start;

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
Patients discontinuing palbociclib/placebo treatment due to treatment-related toxicity may 
continue on the active treatment phase of the study receiving cetuximab monotherapy as per 
the investigator’s discretion.  Patients discontinuing cetuximab treatment due to 
treatment-related toxicity must also discontinue palbociclib/placebo treatment.
5.5.3.1. Cetuximab Dose Modification Guidelines
Dose reduction of cetuximab by 1 and, if needed, 2 dose levels (Table 2) will be allowed 
depending on the type and severity of toxicity encountered.  Patients requiring more than 
2 dose reductions will be discontinued from the study and entered into the follow-up phase.  
All dose modifications/adjustments must be clearly documented in the patient's source notes 
and Investigational product administration CRF.
Table 2.
Cetuximab Available Dose Levels
Dose Level
Cetuximab dose (after 400 mg/m2
loading dose)
Starting Dose
250 mg/m2
-1
200 mg/m2
-2
150 mg/m2
*Cetuximab dose de-escalation below 150 mg/m2 is not allowed.


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5.5.3.1.1. Cetuximab Hypersensitivity Reactions
Mild (Grade 1) hypersensitivity reactions (HSRs) characterized by mild pruritus, flushing, 
rhinitis, rash, and fever are treated with symptom-directed management, including cessation 
of infusion, administration of diphenhydramine 25 mg IVP (may repeat x2), followed by 
famotidine 20 mg IV if symptoms remain after diphenhydramine.  Vital signs should be 
monitored every 15 minutes until symptoms resolve.  Treatment may be restarted at the same 
rate at resolution of symptoms.
Moderate (Grade 2) HSRs consist of generalized pruritus, flushing, rash, back pain, dyspnea, 
hypotension, and rigors.  The infusion should be stopped, and oxygen should be administered 
if the patient is experiencing dyspnea.  Normal saline 500 mL bolus may be given if the 
patient is hypotensive (may repeat as needed).  Diphenhydramine 50 mg IVP should be 
administered, followed by famotidine 20 mg IV followed by hydrocortisone 100 mg IVP 
followed by meperidine 25 mg IV (for rigors).  Vital signs should be monitored every 
2 minutes until stable, then every 15 minutes until symptoms resolve.  Treatment may be 
restarted at resolution of symptoms.
Severe (Grade 3) HSRs are characterized by bronchospasm, generalized urticaria, 
hypotension, and angioedema.  These HSRs should be managed by stopping the infusion and 
administering: normal saline 500 mL bolus (repeat as needed), epinephrine (1:1000) 0.3 mg 
IM, diphenhydramine 50 mg IVP, famotidine 20 mg IV, hydrocortisone 100 mg IVP, and 
albuterol 2.5 mg inhalation (for bronchospasms).  Vital signs should be monitored every 
2 minutes until stable, then every 15 minutes until symptoms resolve.  If cetuximab is 
restarted, restart the infusion rate at 25% of original rate for 30 minutes, then increase to 
50% of infusion rate for the remainder of the infusion.  The infusion rate should be 
permanently reduced by 50%.
Life-threatening/disabling (Grade 4) HSRs consist of anaphylaxis, airway obstruction, shock, 
cardiac arrest, or prolonged hypotension.
Grade 4 HSRs require the immediate interruption of cetuximab therapy and permanent 
discontinuation from further treatment with cetuximab.  Appropriate medical therapy 
including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and 
oxygen should be available for use in the treatment of such reactions.  Patients should be 
carefully observed until the complete resolution of all signs and symptoms.
5.5.3.1.2. Cetuximab Infusion Reactions
Severe infusion reactions (Grade 4) require the immediate interruption of cetuximab therapy 
and permanent discontinuation from further treatment.  Appropriate medical therapy 
including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and 
oxygen should be available for use in the treatment of such reactions.  Patients should be 
carefully observed until the complete resolution of all signs and symptoms.


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Cetuximab recommended dose modifications for infusion reactions:

Reduce the infusion rate by 50% for National Cancer Institute Common Toxicity 
Criteria (NCI CTC v.4.03) Grade 1 or 2 and non-serious Grade 3 infusion reactions;

Immediately and permanently discontinue cetuximab for serious infusion reactions, 
requiring medical internvention and/or hospitalization;

Review the information found in the locally approved package insert for Erbitux;

If a patient experiences recurrent fever following premedication and post-dosing with 
an appropriate antipyretic, the infusion rate for subsequent dosing should be 50% of 
previous rate.
5.5.3.1.3. Cetuximab Dermatological Toxicities
Patients developing dermatologic toxicities while receiving cetuximab should be monitored 
for the development of inflammatory or infectious sequelae, and appropriate treatment of 
these symptoms initiated.  Dose modifications of any future cetuximab infusions should be 
instituted in case of severe (Grade 3) acneiform rash.  Treatment with topical and/or oral 
antibiotics (minocycline 100 mg bid) should be considered.
In patients with mild and moderate skin toxicity, treatment should continue without dose 
modification.
Cetuximab recommended dose modifications for severe (NCI CTC Grade 3 or 4) acneiform 
rash are described in Table 3.
Table 3.
Cetuximab Dose Modifications in the Event of Acneiform Rash
Toxicity (NCI CTC Grade 3 or 4, Version 4.03)
Severe Rash
Cetuximab
Outcome
Dose Modification
1st Occurence Delay Infusion 1 to 2 weeks 
Improvement
No Improvement 
Continue at 250 mg/m2
Discontinue cetuximab
2nd Occurence Delay Infusion 1 to 2 weeks 
Improvement
No Improvement 
Reduce dose to 200 mg/m2
Discontinue cetuximab
3rd Occurence Delay Infusion 1 to 2 weeks 
Improvement
No Improvement 
Reduce dose to 150 mg/m2
Discontinue cetuximab
4th Occurence
Discontinue cetuximab
5.5.3.1.4. Cetuximab Gastrointestinal Adverse Effects
Antiemetic agents may be administered prior to the administration of cetuximab.  Diarrhea 
will be treated symptomatically with antidiarrheal agents.  Should gastrointestinal toxicity 
become severe enough to require hospitalization or outpatient IV fluid replacement, all 
treatment should be discontinued temporarily until the patient’s condition improves.  Patients 
experiencing treatment-related Grade 4 vomiting or diarrhea should have their cetuximab and
palbociclib/placebo treatments permanently discontinued.


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5.5.3.1.5. Cetuximab Pulmonary Adverse Effects
In the event of acute onset (Grade 2) or worsening pulmonary symptoms which are not 
thought to be related to underlying cancer, cetuximab therapy should be interrupted and a 
prompt investigation of these symptoms should occur. Cetuximab retreatment should not 
occur until these symptoms have resolved to Grade 1.  If interstitial lung disease is 
confirmed, cetuximab should be discontinued and the patient should be treated appropriately.
5.5.3.1.6. Cetuximab Renal Adverse Effects
Hypomagnesemia has been reported with cetuximab when administered as a single agent and 
in combination with multiple different chemotherapeutic regimens. Patients receiving 
cetuximab should be monitored for hypomagnesemia. Magnesium repletion may be 
necessary based on clinical judgment.
5.5.3.2. Palbociclib/Placebo Dose Modification Guidelines
5.5.3.2.1. Palbociclib/Placebo Dosing Interruptions/Delays
Patients experiencing treatment-related Grade 4 vomiting, diarrhea, or hypertension should 
have their palbociclib/placebo and cetuximab treatments permanently discontinued.
Patients experiencing the following AEs should have their palbociclib/placebo treatment 
interrupted/delayed: 

Uncomplicated Grade 3 neutropenia (ANC<1000/mm3);

Grade 3 neutropenia (ANC<1000/mm3) associated with a documented infection or 
fever 38.5C;

Grade 4 neutropenia (ANC<500/mm3);

Grade 4 thrombocytopenia (Platelet count <25,000/mm3);

Grade 3 non-hematologic toxicity (including, nausea, vomiting, diarrhea, and 
hypertension only if persisting despite optimal medical treatment);

Grade 4 non-hematologic toxicities (see exceptions of vomiting, diarrhea, or 
hypertension above);

Grade 3 QTc prolongation (QTc 501 msec on at least two separate ECGs).
Appropriate follow up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. Criteria required before treatment can resume are described in 
Section 5.5.3.3.
Doses may be held as needed until toxicity resolution. Depending on when the AE resolved, 
a treatment interruption may lead to the patient missing all subsequent planned doses within 
that same cycle or even to delay the initiation of the subsequent cycle. 


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If the AE that led to the treatment interruption recovers within the same cycle, then re-dosing 
in that cycle is allowed.  Doses omitted for toxicity are not replaced within the same cycle.  
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in Section 5.5.3.4 unless expressly agreed otherwise following discussion 
between the investigator and the sponsor. If a dose reduction is applied in the same cycle, 
the patient will need to return to the clinic to receive new drug supply.
In the event of a treatment interruption for reasons other than treatment-related toxicity
(eg, non-cancer related surgery) lasting >2 weeks, treatment resumption will be decided in 
consultation with the sponsor.
5.5.3.3. Palbociclib/Placebo Retreatment
Retreatment 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 50,000/mm3; 

ANC 1000/mm3 and no fever;

Grade 3 treatment-related non-hematologic AEs (including, nausea, vomiting, 
diarrhea, and hypertension only if persisting despite optimal medical treatment), with 
the exception of alopecia, have recovered to Grade 1 or baseline (or, at the 
investigator’s discretion, Grade 2 if not considered a safety risk for the patient);

Grade 4 treatment-related non-hematologic AEs with the exception of alopecia, have 
recovered to Grade 1 or baseline (or, at the investigator’s discretion, Grade 2 if not 
considered a safety risk for the patient).  Patients experiencing treatment-related 
Grade 4 vomiting, diarrhea, or hypertension should have their palbociclib/placebo and
cetuximab treatments permanently discontinued.  QTc <501 msec and potential 
reversible causes (eg, electrolyte imbalance, concomitant medications known to 
prolong QTc) corrected.  If QTc remains above 480 msec, ECGs should be monitored 
more frequently as per the investigator’s best medical judgment until QTc480 msec.
If a treatment delay results from decline in hematologic parameters, the frequency of blood 
count assessments should be increased as clinically indicated.
If these parameters are met within 2 weeks of treatment interruption or cycle delay, 
palbociclib/placebo may be resumed.  Refer to Section 5.5.3.4 for AEs requiring dose 
reduction at the time of treatment resumption. 
If these parameters have not been met after 2 weeks of dosing interruption (including the 
scheduled 1 week off treatment) or 2 weeks of cycle delay, permanent discontinuation of 
palbociclib/placebo treatment should be considered.  Treatment resumption for patients 
recovering from treatment-related toxicity after >2 weeks of treatment interruption or cycle 
delay but deemed to be deriving obvious clinical benefit per the investigator’s best medical 
judgment is left at the investigator’s discretion.


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If palbociclib/placebo treatment is delayed due to a palbociclib/placebo treatment-related 
toxicity within a cycle, the patient will continue cetuximab treatment and complete the 
28-day cycle.  A new cycle will begin after the end of the standard previous 28-day cycle.  If 
the patient experiences prolonged palbociclib/placebo treatment-related toxicity beyond the 
standard one week break in the 28-day cycle (prior to Day 1 of the next cycle), Day 1 of the 
next cycle will begin when palbociclib/placebo treatment is resumed.  The re-treatment of 
cetuximab will be handled independent of palbociclib/placebo treatment, based upon the dose 
modification guidelines for cetuximab, see Section 5.5.3.1. 
In the event that the start of a new cycle is delayed due to treatment related toxicity, 
procedures required on Day 1 of the given cycle will be performed when palbociclib/placebo 
is resumed.  New cycle Day 1 procedures (ie, physical examination, ECOG performance 
status, ECG, Quality of Life questionnaires, blood chemistry, hematology, urinalysis, 
coagulation, and serum pregnancy test) that were performed prior to knowing the need to 
delay the start of the cycle do not need to be repeated (1) if not required to determine whether 
study drug may be resumed and (2) if performed within 7 days prior to study drug 
resumption.  All tumor assessments will occur as scheduled, independent of treatment delays,
and of cycle start delays.
5.5.3.4. Palbociclib/Placebo Dose Reductions
Following dosing interruption or cycle delay the palbociclib/placebo dose may need to be 
reduced when treatment is resumed.
No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity.  
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances.
Dose reduction of palbociclib/placebo by 1 and, if needed, 2 dose levels (Table 4) will be 
allowed depending on the type and severity of toxicity encountered.  Patients requiring more 
than 2 dose reductions will be discontinued from palbociclib/placebo treatment and entered 
into the follow-up phase.  All dose modifications/adjustments must be clearly documented in 
the patient's source notes and Investigational product administration CRF. 
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.
Table 4.
Palbociclib/Placebo Available Dose Levels
Dose Level
Palbociclib/Placebo for 3 out of 4 Weeks 
(3/1 Schedule)
Starting Dose
125 mg/day (d)
-1
100 mg/d
-2
75 mg/d*
* Palbociclib/placebo dose de-escalation below 75 mg/d is not allowed.


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Palbociclib/placebo recommended dose modifications for treatment related toxicities 
requiring treatment interruption/delay or persisting despite optimal medical treatment are 
described in Table 5.
Table 5.
Palbociclib/Placebo Dose Modifications for Treatment Related Toxicities 
Requiring Treatment Interruption/Delay or Persisting Despite Optimal 
Medical Treatment
Toxicity
Restart palbociclib/Placebo 
Treatment at:
Uncomplicated Grade 3 neutropenia
(ANC<1000/mm3)
Same dose level
Grade 3 neutropenia (ANC<1000/mm3) associated 
with a documented infection or fever 38.5C
1 Dose Level
Grade 4 neutropenia (ANC<500/mm3)
1 Dose Level
Grade 4 thrombocytopenia (Platelet count 
<25,000/mm3)
1 Dose Level
Grade 3 non-hematologic toxicity (including, 
nausea, vomiting, diarrhea, and hypertension only if 
persisting despite optimal medical treatment)
1 Dose Level
Grade 4 non-hematologic toxicity
1 Dose Level (see exceptions of 
vomiting, diarrhea, or hypertension 
in which case patients should have 
their palbociclib/placebo and
cetuximab treatments permanently 
discontinued)
5.5.3.5. QTc Prolongation Management
In the event of QTc prolongation, possible alternative reversible causes such as serum 
electrolytes abnormalities, or usage of concomitant medications with the potential to prolong 
the QTc interval should be evaluated. 
If such reversible causes are identified, then they should be corrected accordingly 
(ie, correction of electrolyte abnormalities with supplements to within normal limits and/or 
discontinuation (if possible) of concomitant medications known to prolong the QT interval). 
Recommended dose modifications in the event of QTc prolongation are provided in Table 6.


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Table 6.
Palbociclib/Placebo Dose Modifications in the Event of QTc Prolongation
Toxicity (NCI CTC Grade, Version 4.03)
Grade 2 QTc prolongation
Grade 3 QTc prolongation
Grade 4 QTc 
prolongation
Reversible 
cause 
identified 
Treat reversible cause.
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc 480 msec.
Continue at the same dose level.(1)
Treat reversible cause 
Withhold treatment until QTc <501 msec.
Resume treatment at the same dose level.
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc 480 msec.  
Permanently 
discontinue
No reversible 
cause 
identified
Initiate more frequent ECG 
monitoring according to 
investigator’s best medical 
judgment until QTc 480 msec.
Continue at the same dose level.(1)
Withhold treatment until QTc <501 msec.
Resume treatment at the next lower dose
level.(2)
Monitor ECG more frequently as per 
investigator’s best medical judgment until 
QTc 480 msec.
Permanently 
discontinue
1.
If the QTc remains above 480 msec more than 2 cycles or if Grade 2 QTc prolongation recurs in the 
absence of other alternative causes or despite correction of alternative causes, dose adjustment and/or 
discontinuation should be considered in consultation with a cardiologist and the study medical monitor, 
taking into account the emerging safety data from palbociclib trials and the investigator’s best medical 
judgment.
2.
If the Grade 3 QTc prolongation occurs again after one dose reduction, further dose adjustment and/or 
discontinuation should be discussed with study medical monitor in consultation with a cardiologist, taking 
into consideration the emerging safety data from palbociclib trials and the investigator’s best medical 
judgment.
5.6. Drug Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under recommended storage conditions and in 
accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
drug label. 
Storage conditions stated in the Study Reference Safety Document (ie, IB or SPC) will be 
superseded by the storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This must be 
captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily evaluation 
for excursions must be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, must be regularly inspected to ensure it 
is maintained in working order. 


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Any excursions from the product label storage conditions must be reported upon discovery.  
The site must actively pursue options for returning the product to labeled storage conditions, 
as soon as possible.  Deviations from the storage requirements, including any actions taken, 
must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered 
excursions. More specific details will be provided to the sites separately.
Site staff will instruct patients on the storage requirements for take home medications.
5.7. Drug Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.
Medication must be kept in a secured locked area at the study site in accordance with 
applicable regulatory requirements.  Returned medication must be stored separately from 
medication that needs to be dispensed.
To ensure adequate records, palbociclib/placebo capsules will be accounted for as instructed 
by the sponsor.  Patients are requested to return previously dispensed containers as well as 
their completed patient diary to the clinic at each visit for accountability purposes even if 
they will not be issued with new medication at that visit.
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented.
5.8. Concomitant Treatments
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator.  Any medications 
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior 
to the start of study treatment and up to 28 days following the last dose of investigational 
product and the reason for their administration must be recorded on the CRF, which includes 
H1 antagonists pre-medication to alleviate cetuximab infusion reacions.  If a patient begins 
new therapy before the 28-day time period is complete, concomitant medication information 
will not be recorded (from the start of the new therapy).


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Routine postoperative care, such as dressing changes, suture removal, drain removal, or 
venous access (central or peripheral), does not need to be recorded.  Anesthetics used for any 
surgical procedures performed during the patient’s participation in the study can be recorded 
as “unspecified anesthesia” on the concomitant treatment records; it is not necessary to list 
the specific anesthetics.  Palliative and supportive care for cancer-related symptoms will be 
offered to all patients in this study.
5.8.1. Prohibited Medications
The following treatments are prohibited throughout the duration of the active treatment 
phase: 

Anticancer agents: No additional investigational or commercial anticancer agents 
such as chemotherapy, targeted therapy, or biological response modifiers, will be 
permitted during the active treatment phase.  In general, any drugs containing “for the 
treatment of SCCHN” on the product insert are not permitted on study.

Strong/Moderate CYP3A inhibitors/inducers: Palbociclib is metabolized to 
multiple metabolites in a qualitatively similar manner in rat, dog and human liver 
microsomes.  In vitro, palbociclib is primarily metabolized by CYP3A4 enzymes.  
Co-administration with drugs that are strong CYP3A inhibitors or inducers in vivo 
has been shown to change the plasma concentrations of palbociclib in humans.  Data 
from a drug-drug interaction (DDI) study in healthy subjects indicate that 
coadministration of multiple 200-mg doses of the strong CYP3A inhibitor 
itraconazole with a single 125-mg palbociclib dose increased palbociclib total 
exposure (AUCinf) and the peak exposure (Cmax) by approximately 87% and 34%, 
respectively, relative to a single 125-mg palbociclib dose given alone.  Data from a 
DDI study in healthy subjects indicate that coadministration of multiple 600-mg 
doses of the strong CYP3A inducer rifampin with a single 125-mg palbociclib dose 
decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a 
single 125-mg palbociclib dose given alone. The concurrent use of the compounds 
listed below is not allowed in the study: 

Strong/Moderate CYP3A inhibitors, including but not limited to amprenavir, 
atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, 
erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, suboxone, telaprevir, telithromycin, verapamil, voriconazole, and 
grapefruit, grapefruit juice or any product containing grapefruit.

Strong/Moderate CYP3A inducers, including but not limited to carbamazepine,
felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifampin, rifabutin, 
rifapentin, and St. John’s wort.

Drugs known to cause QT interval prolongation are prohibited during the active 
treatment phase.  Refer to Appendix 6 for a list of drugs known to predispose to 
Torsade de Pointes.


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5.8.2. Medications Not Recommended 
The following treatments are not recommended throughout the duration of the active 
treatment phase.  Alternative therapies should be considered whenever possible.  If usage of 
the following treatments is deemed necessary, consultation and agreement with the sponsor is 
required prior to treatment initiation. 

The concurrent use of systemic dexamethasone is not recommended. Topical use of 
dexamethasone is permitted.

Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids.  Steroids given as premedication for cetuximab infusion reactions, or
short course of oral steroids, or inhaled/topical steriods are allowed.

The use of herbal medicine is not recommended during the active treatment phase. 
5.9. Concomitant Radiotherapy or Surgery
Any concurrent radiotherapy (except palliative radiotherapy as specified below) or 
cancer-related surgery are prohibited throughout the duration of the active treatment phase of 
the study.  Patients requiring any of these procedures will be discontinued from the active 
treatment phase and will enter the follow-up phase.
Palliative radiotherapy is permitted for the treatment of painful bony lesions provided that the 
lesions were known to be present at the time of study entry and the investigator clearly 
documents that the need for palliative radiotherapy is not indicative of disease progression.  
In view of the current lack of data about the interaction of palbociclib with radiotherapy, 
palbociclib/placebo treatment should be interrupted during palliative radiotherapy, stopping 
1 day before and resuming treatment 1 week after.  For patients with bone involvement, it is 
suggested to institute palliative radiotherapy before study initiation if possible and clinically 
appropriate (eg, lesions at risk for spontaneous micro-fractures or painful lesions).  Palliative 
radiotherapy during the active treatment phase will be considered alternative cancer therapy 
and will result in censoring of the PFS endpoint.  The dates on which palliative radiotherapy 
is administered should be recorded on the appropriate CRFs. 
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and palbociclib required to minimize the risk of 
impaired wound healing and bleeding has not been determined.  Based on the available 
pharmacokinetic data, stopping palbociclib/placebo is recommended at least 7 days prior to 
elective surgery.  Postoperatively, the decision to reinitiate palbociclib/placebo treatment 
should be based on a clinical assessment of satisfactory wound healing and recovery from 
surgery.
6. STUDY PROCEDURES 
Prior to undergoing any study specific procedures (with the exception of certain imaging 
assessments if meeting the criteria defined in Section 6.1), patients must read and sign the 
consent form.  All study procedures and the timing when they must be performed are detailed 
in the Schedule of Activities.  All data obtained for these assessments must be supported in 
the patients' source documentation.


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For the purposes of this trial, 1 cycle is 28 days.  A cycle could be longer than 28 days if 
persistent toxicity delays the initiation of the subsequent cycle.
When scheduled at the same nominal time, triplicate ECGs should be collected prior to any 
blood draws for PK, biomarkers, or safety labs and prior to placement of the IV line for 
cetuximab administration.
6.1. Screening
Voluntary, written, dated, and signed informed consent must be obtained before any study 
specific procedures are performed (with the exception of certain imaging assessments if 
meeting the criteria defined in this section); however, it may be obtained more than 28 days 
before randomization.  See Section 4.1 and Section 4.2 for detailed inclusion and exclusion 
criteria.
Medical and oncological history must include information on prior anticancer treatments.
Baseline tumor related signs and symptoms will be recorded at the C1D1 visit prior to 
initiating treatment and then reported as AEs during the trial if they worsen in severity or 
increase in frequency.
Radiographic tumor assessments (as documented on the Tumor Assessment Requirements 
Flowchart) that were performed before the signing of the informed consent form as routine 
procedures (but within 28 days prior to randomization) do not need to be repeated and may 
be used as baseline assessments, as long as:

The tests were performed per the method requirements outlined in the Tumor 
Assessment Requirements Flowchart, and Section 7.1, and

Appropriate documentation indicating that these radiographic tumor assessments 
were performed as standard of care is available in the patient’s source notes.
Patients must be HPV-negative to participate in this study.  Analytical method is per 
institutional standards.
For details on screening/baseline procedures, see the Schedule of Activities.
6.2. Active Treatment Phase
For details on procedures during the active treatment phase, see the Schedule of Activities. 
Physical examination/vital signs, blood chemistry, hematology, urinalysis, coagulation, and 
12-lead ECG are not required if acceptable screening assessment is performed within 7 days 
prior to randomization.
Patients must agree to use two methods of highly effective contraception throughout the 
study and continue for 6 months after the last dose of cetuximab.  See Section 4.4 for further 
information. 


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Hemoglobin A1c will be measured at C1D1, during the active treatment phase every 
3 months from the date of randomization (ie, Cycle 4 Day 1, Cycle 7 Day 1, Cycle 10 Day 1, 
etc.), and at the End of Treatment visit.  Fasting glucose will be acquired at baseline Cycle 1 
Day 1, Cycle 1 Day 15, and Cycle 2 Day 1.
In the event that the start of a new cycle is delayed due to treatment-related toxicity, 
procedures required on Day 1 of the given cycle will be performed when palbociclib/placebo 
is resumed. New cycle Day 1 procedures (ie, physical examination, vital signs, ECOG 
performance status, ECG, Quality of Life questionnaires, blood chemistry, hematology, 
urinalysis, coagulation, and serum pregnancy test) that were performed prior to knowing the 
need to delay the start of the cycle do not need to be repeated (1) if not required to determine 
whether study drug may be resumed and (2) if performed within 7 days prior to study drug 
resumption.
6.3. End of Treatment Visit
The end of treatment visit will be performed as soon as possible but no later than 4 weeks 
(ie, 28 days) 7 days from last dose of investigational product and prior to the initiation of 
any new anticancer therapy.
For all patients, including patients starting post-study anticancer therapy, 8 weeks after the 
completion of therapy, blood chemistry panel consisting of magnesium, total calcium, and 
potassium must be checked.
Patients must continue to use two methods of highly effective contraception for 6 months 
after the last dose of cetuximab.
For details on procedures to be performed at the End of Treatment visit, see the Schedule of 
Activities.
6.4. Follow-up Visit
After discontinuation of study treatment, post-study survival status (including post study 
anticancer therapies) will be collected approximately every 2 months (7 days) from the last 
dose of study treatment.  Telephone contact is acceptable.
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented disease progression, as per 
RECIST v. 1.1 definitions, will continue to have tumor assessment performed during the 
follow-up visits every 8 weeks (7 days) from the date of randomization until disease 
progression, initiation of new anticancer therapy or discontinuation of patient from overall 
study participation (eg, death, patient's request, lost to follow-up), whichever occurs first. 
For details on follow-up visit procedures, see the Schedule of Activities.


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6.5. Post-Study Patient Interview
Four weeks after discontinuation of study treatment due to progressive disease, patients will 
be asked to complete the EORTC-QLQ-C30 (Appendix 3) and EORTC-QLQ-H&N35 
(Appendix 4) assessments.  For details, see the Schedule of Activities.
6.6. Patient Withdrawal
6.6.1. Active Treatment Phase Discontinuation
The term "interruption" refers to a patient stopping the investigational product during the 
course of the study, but then re-starting it at a later time in the study.  The reason for dosing 
interruption will be collected on the appropriate CRF. 
The term "discontinuation" refers to a patient's withdrawal from the active treatment phase.  
The reason for discontinuation from treatment will be collected on the appropriate CRF. 
Patients may be withdrawn from the active treatment phase in case of:

Disease progression as per RECIST v.1.1; 

Symptomatic deterioration (ie, development of inability to swallow or global 
deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression as per RECIST v.1.1);

Need for additional anticancer therapy not specified in the protocol;

Unacceptable toxicities; 

Investigator conclusion that it is in the patient’s best interest to discontinue therapy 
(eg, poor compliance with either protocol monitoring or with taking the study 
medications, etc.);

Lost to follow-up;*

Patient choice to withdraw from treatment (follow-up permitted by patient);

Withdrawal of patient consent (cessation of follow-up);

Death.
*If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  Lost to follow-up is defined by the inability to reach the patient after a minimum of 
three documented phone calls, faxes, or emails as well as lack of response by the patient to 
one registered mail letter.  All attempts should be documented in the patient’s medical 
records.  If it is determined that the patient has died, the site will use permissible local 
methods to obtain the date and cause of death.  If investigator’s use of third-party 
representative to assist in the follow-up portion of the study has been included in the patient’s 


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informed consent, then the investigator may use a Sponsor retained third-party representative 
to assist site staff with obtaining patient’s contact information or other public vital status data 
necessary to complete the follow-up portion of the study.  The site staff and representative 
will consult publicly available sources, such as public health registries and databases, in 
order to obtain updated contact information.  If after all attempts, the patient remains lost to 
follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the patient’s medical records.
Patient who discontinue from the active treatment phase must have End of 
Treatment/Withdrawal evaluations performed as soon as possible but no later than 4 weeks 
from the last dose of investigational product and prior to initiation of any new anticancer 
therapy.  Data to be collected for the end of study treatment/withdrawal are described in the 
Schedule of Activities. 
Patients who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures.  The only exception to 
this is when a patient specifically withdraws consent for any further contact with him/her or 
persons previously authorized by patient to provide this information.  Patients should notify 
the investigator of the decision to withdraw consent from future follow-up in writing, 
whenever possible.  The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is from further treatment with study 
drug only or also from study procedures and/or post treatment study follow-up, and entered 
on the appropriate CRF page.  In the event that vital status (whether the patient is alive or 
dead) is being measured, publicly available information should be used to determine vital 
status only as appropriately directed in accordance with local law.
If a patient opts to discontinue from the active treatment phase as a result of an unacceptable 
adverse drug reaction, "withdrawal of consent" should not be the reason for discontinuation.  
Instead, the reason for discontinuation of active treatment phase must be recorded as 
"Unacceptable toxicity" and an appropriate action taken must be assigned on the AE CRF to 
the AE leading to the patient’s withdrawal of consent.
6.6.2. Study Discontinuation
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol required schedule of study 
visits or procedures at a given study site.
Patients will be withdrawn from study in the case of:

Withdrawal of consent (ie, refuses tumor assessments or survival status after end of 
treatment);

Lost to follow-up;*

Administrative study closure by sponsor;

Death. 


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*If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  If after three unsuccessful attempts to contact the patient, one of which is by 
registered letter, the patient should be considered “lost to follow-up”.  Steps taken to contact 
the patient (eg, dates of telephone calls, registered letters, etc.) must be clearly documented in 
the source documents.  In any circumstance, every effort should be made to document patient 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
requests the patient to return all unused investigational product(s), request the patient to 
return for a final visit, if applicable, and follow-up with the patient regarding any unresolved 
AEs.
Data to be collected for the end of study treatment/withdrawal are described in the Schedule 
of Activities. 
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
All study procedures are described in the Schedule of Activities table and footnotes.
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he or she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion.
7.1. Efficacy Assessments
7.1.1. Tumor Assessments
The importance of timely and complete disease assessments in this study cannot be 
understated.  Disease assessments must be performed as scheduled according to the calendar, 
regardless of treatment delays resulting from toxicity, to prevent the introduction of bias into 
the assessment of efficacy.  Failure to perform any of the required disease assessments will 
result in the inability to determine disease status for that time point.  A series of incomplete 
disease assessments will result in censoring of the secondary endpoint of PFS back to the 
time of the last full assessment that did not show progression.  Frequent off schedule or 
incomplete disease assessments have the potential to weaken the conclusion of this clinical 
trial.
Objective tumor response will be measured using RECIST v. 1.1.  All measurements should 
be recorded in metric notation using a ruler or calipers.


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MRI of the abdomen can be substituted for CT if MRI adequately depicts the disease.  
However, MRI of the chest should not be substituted for CT of chest even if IV contrast is 
contraindicated.  In such case CT will be performed without contrast.  If MRI is used to 
follow-up bone lesion(s) it must be performed a few days before any treatment that may 
affect bone-marrow cellularity (eg, G-CSF).
7.1.1.1. Screening/Baseline Tumor Assessment
Screening/baseline tumor assessment will be carried out within 28 days before randomization 
(unless otherwise specified below). 
Disease assessment for all patients at baseline will include:

Computed tomography (CT) or magnetic resonance imaging (MRI) scan of the head 
and neck (oral cavity, oropharynx, hypopharynx, larynx);

CT or MRI scan of the chest and abdomen (including the liver);

CT or MRI scan of any other sites of disease as clinically indicated. 
Baseline brain scans are required in patients with a history of metastatic brain disease.  Brain 
scans performed before the signing of informed consent as routine procedures (but within 
6 weeks before randomization) do not need to be repeated and may be used as baseline 
assessments as long as (1) tests were performed using the method requirements outlined in 
RECIST v.1.1 (2) the same technique/modality can be used to follow identified lesions 
throughout the trial for a given patient (3) appropriate documentation indicating that these 
radiographic tumor assessments were performed as standard of care is available in the 
patient’s source notes.  Post-baseline brain scans will be required only if new metastases are 
suspected.
Clinical assessment of superficial disease which will include photographs of all superficial 
metastatic lesions.  All lesion measurements must be recorded in the CRF.
7.1.1.2. Post-Baseline Tumor Assessments
Post-baseline tumor assessments will be performed every 8 weeks (7 days) from 
randomization until radiographically and/or clinically (ie, for photographed or palpable 
lesions) documented PD as per RECIST v.1.1, initiation of new anticancer therapy, or 
discontinuation of patient from overall study participation (eg, death, patient's request, lost to 
follow-up).  Imaging assessments are to be scheduled using the randomization date as the 
reference date for all time-points and are NOT to be scheduled based on the date of the 
previous imaging time-point.  Imaging assessment delay to conform to treatment delay is not 
permitted.
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented disease progression as per 
RECIST definitions will continue to have tumor assessment performed during the follow-up 
visits every 8 weeks (7 days) until documented disease progression, initiation of new 


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anticancer therapy or discontinuation of patient from overall study participation (eg, death, 
patient's request, lost to follow-up), whichever occurs first.  Every effort should be made to 
perform a last tumor assessment before starting a new anticancer therapy.  Additional 
unscheduled tumor assessments may be performed as clinically indicated at any time. 
Post-baseline tumor assessments will include:

Clinical assessment of sites of superficial disease identified at baseline.  Clinical 
assessment of superficial disease must coincide with the imaging studies and will 
include photographs of all superficial metastatic lesions.  All lesion measurements 
must be recorded in the CRF.

The CT scans, including brain CT scan if applicable, should be performed with 
contrast agents unless contraindicated for medical reasons.  If IV contrast is medically 
contraindicated, the imaging modality to be used to follow the disease (either CT 
without contrast or MRI) should be the modality which best evaluates the disease, and 
the choice should be determined by the investigator in conjunction with the local 
radiologist.

CT or MRI scan of the head and neck (oral cavity, oropharynx, hypopharynx, larynx).

CT or MRI scan of the chest and abdomen (including the liver).

CT or MRI scan of any other sites of disease identified at baseline.
The same method and technique should be used to characterize each lesion identified and 
reported at baseline, during the study treatment period and during follow-up.  The use of 
plain-film X-rays is discouraged.  The use of positron emission tomography (PET) imaging 
as the only imaging modality is not permitted.
7.1.2. Overall Survival
Following the End of Treatment visit, survival status will be collected in all patients every 
2 months (7 days) from the last dose of study treatment.  Information on subsequent 
anticancer therapy will also be collected.
7.2. Pregnancy Testing
For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL and assayed in a certified laboratory, will be performed on 2 occasions 
prior to starting study therapy-once at the start of screening and once at the baseline visit, 
immediately before investigational product administration.  A negative pregnancy result is 
required before the patient may receive the investigational product. Pregnancy tests will also 
be routinely repeated at Day 1 of each cycle during the active treatment period, at the End of 
Treatment Visit, and additionally whenever 1 menstrual cycle is missed or when potential 
pregnancy is otherwise suspected. Additional pregnancy tests may also be undertaken if 
requested by IRBs/ECs or if required by local regulations.  In the case of a positive 
confirmed pregnancy, the patient will be withdrawn from study medication and will be 


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withdrawn from the study.  Two methods of highly effective contraception must be used 
throughout the study and continue for 6 months after the last dose of cetuximab.  See 
Section 4.4 for further information.
7.3. Safety Assessments
Safety assessment will consist of monitoring of all AEs, including SAEs, regular monitoring 
of hematology, serum chemistry, and routine monitoring of ECGs, physical examinations, 
vital signs, and ECOG performance status. 
AE assessment will include type, incidence, severity (graded by the NCI CTCAE, 
Version 4.03, Section 8.8), timing, seriousness, and relatedness.
Baseline tumor-related signs and symptoms will be recorded at the Cycle 1 Day 1 visit and 
then reported as AEs during the trial if they worsen in severity or increase in frequency.
7.3.1. Laboratory Safety Assessments
Blood tests will include the following:
Hemoglobin
Chemistry
Hemoglobin
ALT
WBC
AST
Platelets
Alkaline Phosphatase
Absolute Neutrophils
Sodium
Absolute 
Lymphocytes
Potassium
Magnesium
Coagulation
Chloride
PT or INR
Total Calcium
PTT/aPTT
Total Bilirubin *
BUN or Urea
Creatinine
Uric Acid
Glucose (fasted)
HbA1c
Albumin
Phosphorus or Phosphate
*For potential Hy’s law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/INR, and alkaline phosphastase.
Blood tests will be drawn at the time points described in the Schedule of Activities, and 
analyzed at local laboratories.  Additional blood tests may be performed at the investigator's 
discretion as clinically indicated for the purpose of planning treatment administration, dose 
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For all patients, including patients starting post-study anticancer therapy, 8 weeks after the 
completion of therapy, blood chemistry panel consisting of magnesium, total calcium, and 
potassium must be checked.  If abnormalities are observed, an ECG can be performed at the 
discretion of the investigator to check QTc.
Urinalysis will be conducted via urine dipstick for urine protein: if the result is positive, 
further diagnostic testing will be performed as clinically indicated.
Patients must be HPV-negative to participate in this study.  Analytical method is per 
institutional standards.
Refer to the Schedule of Activities for laboratory assessment details.

Electrocardiogram (ECG);

All ECGs will be performed using a 12-lead (with a 10-second rhythm strip) tracing.  
ECG measurements will include PR interval, QT interval, RR interval, and QRS 
complex.  It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically. 
ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination and patient safety monitoring and 
documentation stored in the source documents. 
Triplicate ECGs will be performed for all patients. 

All ECGs should be obtained after a fast of at least 1 hour.  When scheduled at the 
same nominal time/visit, triplicate ECGs should be collected prior to any blood draws 
for PK, biomarkers, or safety labs and prior to placement of the IV line for cetuximab 
administration.

Triplicate ECGs will be obtained for safety monitoring at Screening, and 0 hour 
(palbociclib pre-dose) on C1D1, C1D15 and C2D15, then on Day 1 of Cycles 4, 7, 
and 10.  ECGs will be obtained at the time of End of Treatment or Withdrawal.  
ECGs beyond Cycle 10 will be performed as clinically indicated.
Additional ECGs may be performed as clinically indicated at any time.
For the purpose of the study, triplicate ECGs are defined as three consecutive ECGs 
performed approximately 2 minutes apart but within 10 minutes for all 3 ECGs at the 
protocol specified timepoints (see the Schedule of Activities for details) to determine the 
mean QTc interval. 
If at any time during the course of treatment, the mean QTc is prolonged (501 msec on at 
least two separate ECGs, ie, CTCAE Grade 3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate.  If manual reading confirms a QTc of 


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501 msec, immediate search for reversible causes (including electrolyte abnormalities, 
hypoxia and concomitant medications for drugs with the potential to prolong the QTc 
interval) should be performed.  In addition, repeat ECGs should be immediately performed 
hourly for at least 3 hours until the QTc interval falls below 501 msec. 

If QTc interval reverts to less than 501 msec, and in the judgment of investigator(s) in 
consultation with the sponsor the cause is determined to be other than study drug, 
treatment may be continued with regular ECG monitoring under hospital supervision. 

If in that timeframe the QTc intervals remain above 501 msec the study drug will be 
held until the QTc interval decreases to <501 msec. 
Prior to concluding that an episode of prolongation of the QTc interval is due to study drug, 
thorough consideration should be given to potential precipitating factors (eg, change in 
patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If investigational product causality cannot be ruled out, Investigational product dose 
adjustment and/or discontinuation should be performed according to instructions provided in 
Section 5.5.3.  Additional triplicate ECGs may be performed as clinically indicated. 
When matched with PK sampling, ECG must be carried out before PK sample drawing such 
that the PK samples are collected at the nominal time (ie, the timing of the PK collections 
over rides the timing of the ECG collections).
7.3.2. Other Safety Assessments
A full physical examination including an examination of all major body systems (including
head, ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and 
musculoskeletal), height (at screening only), weight, blood pressure and pulse rate which
may be performed by a physician, registered nurse or other qualified health care provider, 
will be required at screening, and Day 1 of Cycles 1 and 2. 
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits.
Performance Status: ECOG performance status scale will be used (see Appendix 5).
 
 
 
 
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The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the pharmacokinetic samples at the exact nominal time relative to 
dosing.  However, pre-infusion samples drawn within 30 minutes of the start of infusion and 
post-infusion samples collected within 10% of the planned nominal time (eg, within 
6 minutes of the end of a 60 minute infusion) from dosing will not be captured as protocol 
deviations, as long as the exact time of the sample collection and the exact infusion start/stop 
times are noted on the source document and data collection tool (eg, CRF).
One 3 mL sample of venous blood, to provide a minimum of 1 mL serum for PK analysis,
will be collected into appropriately labeled collection tubes containing no additives at the 
protocol-specified times.  Samples will be kept in an ice bath prior to processing.
Samples will be analyzed for cetuximab using a validated analytical method in compliance 
with Pfizer standard operating procedures. 
As part of understanding the pharmacokinetics of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method.  These data will be 
used for internal exploratory purposes and will not be included in the Clinical Study Report.
Samples collected for this purpose will be retained in accordance to local regulations and if 
not used within this timeframe, will be destroyed.
Additional blood samples may be requested from patients experiencing unexpected or serious 
AEs, or AEs that lead to discontinuation.
Blood samples for PK assessments of cetuximab will be collected from all participating
patients prior to IV infusion (pre-dose) and immediately prior to completion of the IV 
infusion (post-dose) on Day 15 of Cycles 1 and 2. In the event a pre-dose or post-dose 
sample cannot be/is not collected on Day 15 of Cycle 1 or Cycle 2 as scheduled, every effort 
should be made to collect a makeup sample on Day 22 of the same cycle or on Day 15 or
Day 22 of any subsequent cycles beyond Cycle 2 following the same rules described above.  
Blood samples for post-dose PK assessments of cetuximab should not be collected from the 
same arm that the cetuximab IV infusion was administered.
When assessments are scheduled on the same visit, whenever possible, efforts should be 
made to coordinate collection of pre-infusion PK and biomarker blood draws within a 
30-minute window.
Refer to the Study Manual for detailed collection, processing and shipping procedures.
7.5. Biomarker Assessments
Archival tumor tissues are required from all patients for study participation. 
Submission of formalin-fixed paraffin embedded (FFPE) tumor samples (blocks preferred) of 
adequate size (to generate at least 15 sections of 5-micron each) are needed.  If FFPE tissue 
block cannot be provided, a minimum of 15 glass slides each containing an unstained 


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5-micron FFPE tissue section, will be required for patient participation.  If an archival tumor 
tissue sample is not available, a de novo tumor specimen must be obtained.  Specimens will 
be sent to the Sponsor-designated central laboratory.  Details for the handling of these 
specimens, including processing, storage, and shipment will be provided in the Study 
Manual.  Table 7 summarizes the biomarker assessments currently planned for the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.
7.7. Patient Reported Outcomes
Patient reported outcomes of health-related quality of life and health status will be assessed 
using the EORTC-QLQ-C30, and EORTC-QLQ-H&N 35 instruments. 
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Patients will complete each instrument at pre-dose on Day 1 of Cycles 1-3, then on Day 1 of 
every other subsequent Cycle starting with Cycle 5 (eg, Cycles 5, 7, 9, etc.), and then at the 
End of Treatment visit.  This schedule is based on the schedule for the assessment of clinical 
activity.  Four weeks after discontinuation of study treatment due to progressive disease, 
patients, including patients starting post-study anticancer therapy, will be completing the 
quesstionaires at the Follow-up Visit.
Patients must complete these instruments in clinic (cannot be taken home) and prior to 
having any tests and to any discussion of their progress with healthcare personnel at the site.  
Interviewer administration in clinic may be used under special circumstances (eg, patient 
forgot their glasses or feels too ill), but family members are not permitted to assist with 
questionnaire administration.  The instruments will be given to the patient in the appropriate 
language for the site. 
7.7.1. European Organisation for Research and Treatment of Cancer Quality of Life 
Instrument (EORTC QLQ-C30) (Appendix 3)
The EORTC QLQ C30 is a 30 item questionnaire composed of five multi item functional 
subscales (physical, role, cognitive emotional, and social functioning), three multi item 
symptom scales (fatigue, nausea/vomiting, and pain), a global health/quality of life (QOL) 
subscale, and six single items assessing other cancer related symptoms (dyspnea, sleep 
disturbance, appetite, diarrhea, constipation, and the financial impact of cancer).  The 
questionnaire employs 28 4 point Likert scales with responses from “not at all” to “very 
much” and two 7 point Likert scales for global health and overall QOL.  For functional and 
global QOL scales, higher scores represent a better level of functioning and are converted to 
a 0 to 100 scale.  For symptom oriented scales, a higher score represents more severe 
symptoms.
7.7.2. European Organisation for Research and Treatment of Cancer Head and Neck 
Module 35 (EORTC QLQ-H&N35) (Appendix 4)
The EORTC QLQ-H&N35 is designed to be used together with the core QLQ-C30.  The 
time frame of the module is ‘‘during the past week,’’ and the format is similar to that of the 
core questionnaire.  Items hn 1 to hn30 are scored on four-point Likert-type categorical 
scales (‘‘not at all,’’ ‘‘a little,’’ ‘‘quite a bit,’’ ‘‘very much’’).  Items hn31 to hn35 have a 
‘‘no/yes’’ response format.  The scores are transformed into 0-to-100 scales, with a high 
score implying a high level of symptoms or problems, in the same way as scoring for 
symptom scales and single items of the QLQ-C30.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 


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For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.
AEs (serious and nonserious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product through the patient’s last visit.
If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends 
at the time the new treatment is started.  Death must be reported if it occurs during the SAE
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;


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
Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, at the wrong dosage strength, or 
inadvertent exposure.  Such medication errors occurring to a study participant are to be 
captured on the medication error CRF which is a specific version of the AE page, and on the 
SAE form when appropriate.  In the event of medication dosing error, the sponsor should be 
notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 5 (see the section on Severity Assessment).


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in asparate aminotransferase (AST) and/or alanine aminotransferase (ALT)
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).
Concurrent with

For patients with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN or
if the value reaches 3 X ULN (whichever is smaller).


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The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, physical assessment, and primary or secondary 
hepatic neoplasia should be considered.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 


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
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed below.
Investigators report AEs using concise medical terminology (verbatim) as well as collect on 
the CRF the appropriate Common Terminology Criteria (CTC) term for AEs (Version 4.03, 
Publish Date:  June 14, 2010, http://ctep.cancer.gov/reporting/ctc.html)) listed in the Cancer 
Therapy Evaluation Program. 
The investigator will use the following definitions of Severity in accordance with the current 
CTC Version to describe the maximum intensity of the AE.


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GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD AE
2
MODERATE AE
3
SEVERE AE
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO AE
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.


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If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on a SAE Report Form and EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure. The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays). In the case of paternal 
exposure, the investigator will provide the study patient with the Pregnant Partner Release of 
Information Form to deliver to his partner. The investigator must document in the source 
documents that the patient was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to the drug safety unit within 24 hours of the
Investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE. Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF, however a copy of the completed SAE Report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also Section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient/legally acceptable representative.  In addition, each study patient/legally 
acceptable representative will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding and occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 


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medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF. Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  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.
9.1. Sample Size Determination
The primary objective of this study is to demonstrate that the combination of palbociclib with 
cetuximab is superior to cetuximab in prolonging OS in the target population.  This study is 
designed to test the null hypothesis of equal survival between the treatment arms versus the 
alternative hypothesis of improved survival in the palbociclib + cetuximab arm compared 
with the placebo + cetuximab arm.
Assuming a median OS of 6 months in the comparator arm, approximately 79 total events
(deaths) are required for 1:1 randomization to have at least 80% power to detect a true hazard 
ratio of 0.6 (corresponding to a median OS of 10 month in the palbociclib arm) using a 
one-sided, log-rank test at a significance level of 0.1.  The formal futility boundary will be 
constructed using the Gamma family of spending function with parameter = 0.05.  With 
40 observed events at the interim analysis, the futility boundary is p-value = 0.36 
(corresponding to HR = 0.9). The boundary at final analysis is p-vlaue = 0.1.
Approximately 120 patients will be enrolled in about 16 months and followed for additional
6 months to observe the required number of events.  This estimation is based on the 
following assumptions on the enrollment rates: 1) 5 patients per month (on average) during 
the first 6 months; 2) 10 patients per month (on average) thereafter.


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9.2. Efficacy Analysis
9.2.1. Analysis of Primary Endpoint
All randomized patients will be included in this analysis.  Survival time is defined as the time 
from the date of randomization to the date of death.  Since the date of randomization and the 
date of death should be counted as a full day, 1 day will be added to each calculation.  
Patients alive will have their survival times censored on the last date of known contact that 
the patient was documented to be alive.  Patients lacking data beyond the day of 
randomization will have their survival times censored at Day 1. 
For each arm, estimates of the survival curves from the Kaplan-Meier method will be 
presented.  Median survival times and 2-sided 95% and 80% confidence intervals (CIs) for 
the medians will be provided using the Brookmeyer-Crowley method.  The survival 
probabilities at 4, 6 and 12 months will be estimated.
Differences in survival between treatment arms will be tested using the stratified log-rank 
test where the stratification factors are ECOG performance status (0 vs. 1) and prior use of 
immunotherapy (yes vs. no).  The stratisfied analysis will be the primary analysis.  As a 
sensitivity analysis, the unstratified log-rank analysis will also be performed.  The hazard 
ratio estimates and their 95% and 80% CIs will be generated using stratified and unstratified 
Cox proportional hazards models.  Rank-preserving structural failure time (RPSFT) method, 
as supportive/exploratory analysis for OS, will also be conducted.
9.2.2. Analysis of Secondary Endpoints
9.2.2.1. Progression-Free Survival
PFS which is defined as the time from the date of randomization to the date of the first 
documentation of objective progression of disease (PD) or death due to any cause, whichever 
is earlier.  For patients who do not have objective tumor progression and who do not die 
while on study, PFS data will be censored on the date of the last adequate tumor assessment 
on study.  Patients lacking an evaluation of tumor response after randomization will have 
their PFS time censored on the date of randomization with duration of 1 day. 
For each arm, estimates of the PFS curves from the Kaplan-Meier method will be presented.  
Median PFS and 2-sided 95% and 80% CIs for the medians will be provided using the 
Brookmeyer-Crowley method.  The PFS probabilities at 4, 6 and 12 months will be 
estimated.
Differences in PFS between treatment arms will be tested using the unstratified log-rank test.  
The hazard ratio estimates and their 95% and 80% CIs will be generated using unstratified 
Cox proportional hazards models.


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9.2.2.2. Objective Response
Objective response (OR) is defined as a CR or PR according to RECIST v. 1.1.  
Confirmation of the response is required.  The ORR is defined as the percentage of patients 
with a CR or PR.  Patients who die, progress, or drop out for any reason after randomization 
prior to documented response will be included in the analysis as non-responders.
ORR on each treatment arm will be estimated with exact 2-sided 95% and 80% CIs.  
Treatment effects in terms of risk ratio will be tested using Cochran-Mantel-Haenszel (CMH) 
test with the same stratification factors as for the OS analysis.  Ninety-five percent and 80% 
CIs will also be provided. 
9.2.2.3. Duration of Response
DR will be analyzed for patients who achieve a best overall response of CR or PR per 
RECIST v. 1.1.  DR is defined as the time from the first documentation of objective tumor 
response (CR or PR) to the first documentation of objective tumor progression or death due 
to any cause, whichever is earlier.  The same censoring rules for PFS will be applied to DR. 
For each arm, estimates of the DR curves from the Kaplan-Meier method will be presented.  
Median DR times and 2-sided 95% and 80% CIs for the medians will be provided using the 
Brookmeyer-Crowley method. 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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9.3.2. Biomarkers
9.3.2.1. Biomarker Analysis Set
The biomarker analysis set is defined as all patients treated with cetuximab in combination 
with placebo or palbociclib who have at least one baseline biomarker assessment.  Analysis 
sets will be defined separately for
, archival tumor tissue
 
 
9.3.2.2. Statistical Analysis of Biomarker Endpoints
Biomarkers will be assessed separately 
, archival tumor tissue 
 
  In each case, summaries of baseline levels, changes from baseline (where 
appropriate), expression and mutation will be reported.  For continuous variables, summary 
statistics may include the mean, ratio to baseline, standard deviation, 25th median, and 
75th quartile, % CV, and minimum/maximum levels of biomarker measures; for categorical 
variables, summary may include number and percentage, odds ratio as appropriate. 
 
 
 
 
9.3.3. Patient-Reported Outcomes (PROs)
Health-Related Quality of life and Head and Neck scores and change from baseline scores 
will be compared between the treatment arms using a mixed model repeated measures 
approach adjusting for specified covariates.  In addition, analyses will be performed to 
determine if the change from baseline scores achieve the appropriate minimally important 
difference (MID) cut-off for the scale being examined. 
In addition to the above analyses, an examination of the time to deterioration (TTD) 
composite endpoint will be carried out using survival analysis methods.  A composite 
definition for deterioration based on death, tumor progression, and/or SCCHN
cancer-specific quality of life subscale MIDs may be used.
CCI
CCI
CCI
CCI
CCI


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9.4. Safety Analysis
All patients who receive any study treatment will be included in the final summaries and 
listings of safety data.  In addition, the relationship between exposure and efficacy and safety 
endpoints will be explored, as necessary, based on emerging efficacy and safety data.  Refer 
to SAP for details of the analyses. The results of these modeling analyses may be reported 
separately from the clinical study report.
9.4.1. Adverse Events
Frequencies of patients experiencing at least 1 AE will be summarized by system organ class 
(SOC) and preferred term according to MedDRA terminology.  The number and percent of 
patients with AE will be tabulated by treatment and by cycle. 
Detailed information collected for each AE will include: a description of the event; duration; 
whether the AE was serious; intensity (severity) of event; relationship to study drug; action 
taken; and clinical outcome.  Intensity (severity) of the AEs will be graded according to NCI 
CTCAE version 4.03. 
AEs leading to death or discontinuation of treatment, classified as Grade 3, or drug related, 
and SAEs will be considered with special attention.
9.4.2. Laboratory Abnormalities
Hematology and chemistry laboratory data will be summarized by treatment and by cycle.  
The laboratory results will be graded according to the NCI CTCAE v4.03 severity grade.  
The frequencies of the worst severity grade observed will be displayed by study treatment.  
Shift tables will be provided to examine the distribution of laboratory toxicities.  For 
parameters for which an NCI CTCAE v4.03 scale does not exist, the frequency of patients 
with values below, within, and above the normal ranges will be summarized by treatment.
9.4.3. Electrocardiogram (ECG)
For the analysis of ECG data, the triplicate data will be averaged and all summary statistics 
and data presentations will use the triplicate averaged data.  Any data obtained from ECGs 
repeated for safety reasons after the nominal time-points will not be averaged along with the 
preceding triplicates.
For all patients in the safety analysis set, individual changes in QTc (QTcF, QTcB and 
QTcS) will be calculated for each nominal post-baseline time point and summarized using 
descriptive statistics.  Categorical analysis of the QTc data will be performed as follows:

The number and percentage of patients with maximum increase from baseline in QTc 
(<30, 30-60, and 60 msec).

The number of and percentage patients with maximum post-dose QTc 
(<450, 450-<480, 480-<500, and >500 msec).


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
The number of and percentage patients with PR changes from baseline 50% if 
absolute baseline value was <200 msec, and 25% if absolute baseline value was 
>200 msec.

The number of and percentage patients with QRS changes from baseline 50% if 
absolute baseline value was <100 msec, and 25% if absolute baseline value was 
>100 msec.

The number and percentage of individuals with abnormal ECG findings.
9.5. Interim Analysis
An interim analysis will be performed when at least 50% of the required number of events
(40 deaths) is observed. The purpose of this interim analysis is to stop the study early for
futility.  The formal futility boundary will be constructed using the Gamma family of 
spending function with parameter = 0.05.  With 40 observed events at the interim analysis, 
the futility boundary is p-value = 0.36 (corresponding to HR = 0.9). The boundary at final 
analysis is p-vlaue = 0.1.
9.6. Data Monitoring Committee 
This study will use an E-DMC. 
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of patients 
in the study according to the Charter. The E-DMC will make recommendation as to whether 
or not the trial should continue based on ongoing reviews of safety data.  In addition, the 
E-DMC will also evaluate interim efficacy data and make a recommendation regarding study 
continuation based on observed results of the study. The recommendations made by the 
E-DMC to alter the conduct of the study will be forwarded to Pfizer for final decision.  Pfizer 
will forward such decisions, which may include summaries of aggregate analyses of endpoint 
events and of safety data that are not endpoints, to regulatory authorities, as appropriate.  The 
sponsor will designate a biostatistician not affiliated with the project to prepare data for 
E-DMC review.  Only if action or consultation with Health Authorities is required will other 
sponsor staff be involved.  Clinical sites will be restricted from access to study results until 
the conclusion of the study.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be patient to review by the IRB/EC, and/or to quality assurance audits 
performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to inspection 
by appropriate regulatory authorities.


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It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to International Conference on Harmonisation 
(ICH), according to local regulations, or as specified in the clinical study agreement (CSA), 
whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 


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Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data is compiled for transfer to Pfizer and other authorized parties, patient
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients. The study 
site will maintain a confidential list of patients who participated in the study linking their 
numerical code to the patient’s actual identity.  In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of patient personal data consistent with 
applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.


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The informed consent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study patient, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, then 
the patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his/her own consent, the source documents
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse) and that the patient’s assent was obtained, or waived.  If assent is obtained verbally it 
must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative before any 
study-specific activity is performed, unless a waiver of informed consent has been granted by 
an IRB/EC. The investigator will retain the original of each patient's signed consent 
document.
12.4. Patient Recruitment
Advertisements approved by ECs and investigator databases may be used as recruitment 
procedures. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 


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in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last patient last visit (LPLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of palbociclib at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within one week of notification.  As directed by Pfizer, 
all study materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.


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EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to on www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the investigational 
drug. However, to ensure against inadvertent disclosure of confidential information or 
unprotected inventions, the investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, the investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information (other than the study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, the investigator is free to publish separately, patient to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.


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Dickson MA, Tap WD, Keohan ML, D'Angelo SP, Gounder MM, Antonescu CR, 
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Appendix 1. Adkins, D. Protocol # 201404139
Adkins D, Lewis J, Michel L, Trinkaus K, Wildes T. Phase I/II Trial of the Addition of 
PD 0332991 to Cetuximab in Patients with Incurable SCCHN. Washington Univeristy 
School of Medicine, Division of Oncology Protocol # 201404139, Version Date 05/06/2014.


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Appendix 2. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions 

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical examination that are not measurable 
by reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
Recording Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 

If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used.

Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded.
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 


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Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
< 10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed. 

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate.  Progression has not been documented, and 

one or more target measurable lesions have not been assessed, 

or assessment methods used were inconsistent with those used at baseline,

or one or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure),

or one or more target lesions were excised or irradiated and have not reappeared 
or increased. 
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 


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
Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
Table 1. Objective Response Status at each Evaluation 
   Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 2. Objective Response Status at each Evaluation for Patients with Non-Target Disease 
Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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Appendix 3. European Organisation for Research and Treatment of Cancer Quality of 
Life Instrument (EORTC-QLQ-C30)


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Appendix 4. European Organisation for Research and Treatment of Cancer Head and 
Neck Module 35 (EORTC-QLQ-H&N35)


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Appendix 5. Eastern Cooperative Oncology Group (ECOG) Performance Status
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, 
ie, 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 6. List of Drugs Known to Predispose to Torsade de Pointes
Generic Name
Brand Name(s)
Amiodarone
Cordarone, Pacerone
Arsenic trioxide
Trisenox
Astemizole
Hismanal
Azithromycin
Zithromax
Bepridil
Vascor
Chloroquine
Aralen
Chlorpromazine
Thorazine
Cisapride
Propulsid
Citalopram
Celexa
Clarithromycin
Biaxin
Disopyramide
Norpace
Dofetilide
Tikosyn
Domperidone
Motilium
Droperidol
Inapsine
Erythromycin
Erythrocin, E.E.S.
Flecainide
Tambocor
Halofantrine
Halfan
Haloperidol
Haldol
Ibutilide
Corvert
Levomethadyl
Orlaam
Mesoridazine
Serentil
Methadone
Dolophine, Methadose
Moxifloxacin
Avelox
Ondansetron*
Zofran
Pentamidine
Pentam, NebuPent
Pimozide
Orap
Probucol
Lorelco
Procainamide
Pronestyl, Procan
Quinidine
Cardioquin, Quinaglute
Sotalol
Betapace
Sparfloxacin
Zagam
Terfenadine
Seldane
Thioridazine
Mellaril
Vandetanib
Caprelsa
*when administered intravenously at high dose (32 mg).
Adapted from the University of Arizona Cancer Center for Education and Research on Therapeutics: "Torsades 
List: Drugs with a Risk of Torsades de Pointes," drugs that are generally accepted by the QTdrugs.org Advisory 
Board to carry a risk of Torsades de Pointes on the University of Arizona CERT website: 
http://www.crediblemeds.org/.  This list is not meant to be considered all inclusive.  See website for current list. 


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Appendix 7. Bone Marrow Reserve in Adult
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol.  5, 255-258, 1961
Marrow Distribution of the Adult
SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head:
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle :
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs: 
82.6
1 pair
10.2
All 0.4
4.1
2 
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8


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MARROW DISTRIBUTION OF THE ADULT (CONT'D)
SITE
MARROW
wt. (g)
FRACTION RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8
Vertebrae
(Lumbar):
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0

SAP_000.pdf: 
Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 1 
Protocol A5481044
A Randomized, Multicenter, Double-blind Phase 2 Study of Palbociclib 
plus Cetuximab versus Cetuximab for the Treatment of Human 
Papillomavirus-negative, Cetuximab-naïve Patients with 
Recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck 
after Failure of One prior Platinum-containing Chemotherapy Regimen 
Statistical Analysis Plan  
(SAP)
Version: 
3
Author:
Date:  
April 26, 2018 
PPD


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 2 
TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSION(S) .................................................................5 
2. PER THE CHANGES IN PROTOCOL AMENDMENT 2 (31 MARCH 2016) AND
ONCOLOGY STATISTICS RULEBOOK V3, THE REVISES ARE 
INCORPORATE IN THE AMENDED SAP.   INTRODUCTION ......................................5 
2.1. Study Design ...................................................................................................................6 
2.2. Study Objectives .............................................................................................................7 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ........................................8 
4. HYPOTHESES AND DECISION RULES .................................................................................9 
4.1. Statistical Hypotheses .....................................................................................................9 
4.2. Sample Size Determination and Statistical Decision Rules ............................................9 
5. ANALYSIS SETS .....................................................................................................................10 
5.1. Intent-to-Treat Population (Full Analysis Set) ..............................................................10 
5.2. As-Treated (AT) Population (Safety Analysis Set) .......................................................10 
5.3. Other Analysis Sets .......................................................................................................10 
5.3.1. Pharmacokinetic Analysis Set ..........................................................................10 
5.3.2. Biomarker Analysis Set ....................................................................................10 
5.3.3. Patient Reported Outcome (PRO) Analysis Set ...............................................11 
5.4. Treatment Misallocations ..............................................................................................11 
5.5. Protocol Deviations .......................................................................................................11 
5.5.1. Protocol Deviations Assessed Prior to Randomization ....................................11 
5.5.2. Protocol Deviations Assessed Post Randomization .........................................11 
6. ENDPOINTS AND COVARIATES .........................................................................................12 
6.1. Efficacy Endpoints ........................................................................................................12 
6.1.1. Primary Endpoint ..............................................................................................12 
6.1.2. Secondary Endpoints ........................................................................................12 
6.2. Safety Data ....................................................................................................................14 
6.2.1. Treatment Emergent Adverse Event .................................................................15 
6.2.2. Treatment Related Adverse Event ....................................................................15 
6.2.3. Laboratory Safety Assessments ........................................................................15 
6.2.4. Electrocardiogram (ECG) .................................................................................16 
6.2.5. Other Safety Assessment ..................................................................................17 
 
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6.3.1. Pharmacokinetic Data .......................................................................................17 
6.3.1.1. Palbociclib Pharmacokinetic Data...................................................17 
6.3.1.2. Cetuximab Pharmacokinetic Data ...................................................18 
6.3.2. Biomarkers ........................................................................................................19 
6.3.3. Patient Reported Outcome Endpoints ...............................................................19 
6.3.3.1. European Organisation for Research and Treatment of 
Cancer Quality of Life Instrument (EORTC QLQ-C30) ...............20 
6.3.3.2. European Organisation for Research and Treatment of 
Cancer Head and Neck Module 35 (EORTC 
QLQ-H&N35) ................................................................................20 
6.4. Covariates and Stratification Factors ............................................................................20 
6.4.1. Covariates .........................................................................................................20 
6.4.2. Stratification Factors .........................................................................................20 
7. HANDLING OF MISSING VALUES ......................................................................................20 
7.1. Missing Dates ................................................................................................................20 
7.2. Missing Tumor Assessments .........................................................................................21 
7.3. Missing Data in PFS Derivation ....................................................................................21 
7.4. Missing QTc Data .........................................................................................................22 
7.5. Missing Patient Reported Outcome Data ......................................................................22 
7.6. Missing PK Samples .....................................................................................................22 
7.7. Missing/Duplicate Biomarker Data ...............................................................................22 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ................................23 
8.1. Statistical Methods ........................................................................................................23 
8.1.1. Analyses for Time-to-Event Data .....................................................................23 
8.1.2. Analyses of Binary Data ...................................................................................23 
8.1.3. Analyses of Continuous Data ...........................................................................24 
8.1.4. Analyses for Categorical Data ..........................................................................24 
8.1.5. Analyses for QTc Data .....................................................................................24 
8.1.5.1. Derived Analysis Variables .............................................................24 
8.1.5.2. Derivation of Study Specific QT Correction Factor .......................24 
8.1.5.3. Assessment of QT Correction Methods ..........................................25 
8.1.5.4. Change from Baseline Definition ....................................................25 
8.1.5.5. Outlier Analysis ...............................................................................26 


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 4 
8.2. Statistical Analyses .......................................................................................................26 
8.2.1. Primary Efficacy Analysis ................................................................................27 
8.2.2. Secondary Analyses ..........................................................................................27 
8.2.3. Sensitivity Analyses for PFS ............................................................................28 
8.2.4. Standard Analyses ............................................................................................29 
8.2.5. Safety Analyses ................................................................................................30 
8.2.5.1. Adverse Events ................................................................................30 
8.2.5.2. Laboratory abnormalities ................................................................32 
8.2.6. QTc Analyses ....................................................................................................32 
8.2.7. Pharmacokinetic and Pharmacodynamic Analyses ..........................................33 
8.2.8. Biomarkers Analyses ........................................................................................34 
8.2.9. Patient Reported Outcomes Analyses ...............................................................35 
8.2.9.1. EORTC QLQ-C30 ...........................................................................36 
8.2.9.2. EORTC QLQ-H&N35 ....................................................................36 
8.3. Summary of Key Clinical Efficacy Analyses ...............................................................37 
9. REFERENCES ..........................................................................................................................38 
10. APPENDICES .........................................................................................................................39 
10.1. Schedule of Activities .................................................................................................39 
10.2. Tumor Assessment Requirements Flowchart ..............................................................44 
10.3. RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 
Guidelines ...................................................................................................................46 
10.4. Rules for Determining PFS Status and Date ...............................................................51 
10.5. Data Derivation Details ...............................................................................................52 
10.6. Study Treatment Modification and Compliance .........................................................53 
10.6.1. Dose Modification ..........................................................................................53 
10.6.2. Summarizing Relative Dose Intensity (RDI) ..................................................53 
10.7. European Organisation for Research and Treatment of Cancer Quality of 
Life Instrument (EORTC-QLQ-C30) .........................................................................57 
10.8. European Organisation for Research and Treatment of Cancer Head and 
Neck Module 35 (EORTC-QLQ-H&N35) .................................................................60 
10.9. List of Abbreviation ....................................................................................................62 


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 5 
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
Version 2: 
Per Protocol amendment 2, removing mITT population from the analysis set. 
Specifying the secondary endpoints by using unstratified log-rank test. 
Adding definition for BOR 
Revising RDI (Relative Dose Intensity) definition  
Specifying the 2 consecutive assessments for tumor assessment to 18 weeks. 
Adding more timeline details for Palbociclib pharmacokinetic and biomarkers data. 
Version 3: 
Adding clinical benefit response (CBR) as second efficacy endpoint.  
Adding clear definition on Study Day and Treatment Day 
2.  PER THE CHANGES IN PROTOCOL AMENDMENT 2 (31 MARCH 2016) AND 
ONCOLOGY STATISTICS RULEBOOK V3, THE REVISES ARE INCORPORATE 
IN THE AMENDED SAP.   INTRODUCTION 
This document describes the planned statistical analyses for Protocol A5481044 dated 
February 7, 2015. This analysis plan is meant to supplement the study protocol.  Any 
deviations from this analysis plan will be described in the Clinical Study Report.  
Combinatorial efficacy was observed following treatment with palbociclib and inhibitors of 
the EGFR pathway, including cetuximab, in preclinical models.  In a panel of 24 SCCHN 
cell lines the palbociclib combination with cetuximab produced synergistic growth inhibition 
in 50 % of models. The combination of palbociclib and cetuximab in a subset of these cell 
lines demonstrated increased inhibition of retinoblastoma protein and downstream 
transcription factor E2F signaling, leading to greater inhibition of new DNA synthesis and 
increased hallmarks of cellular senescence than with each agent alone. In vivo studies in 
patient-derived xenografts demonstrated the ability of either single agent to produce > 90% 
tumor growth inhibition in distinct models, and in a model that failed to show significant 
response to either single agent, the combination of palbociclib and cetuximab yielded 
synergistic tumor growth inhibition. 
In an ongoing Phase 1 clinical trial of escalating doses of palbociclib added to fixed-dose 
cetuximab, one partial tumor response was observed in a patient with SCCHN resistant to 
cetuximab and cisplatin.  Disease control (partial response [PR] or stable disease [SD])
occurred in 6 of the 7 evaluable patients.  Of the 6 patients with cetuximab-resistant SCCHN, 
5 experienced disease control with combined palbociclib + cetuximab treatment. Of the 4 
patients with cisplatin-resistant SCCHN, 3 experienced disease control with palbociclib + 
cetuximab.
The current Phase 2 study provides the opportunity to test the hypothesis that the addition of 
palbociclib to cetuximab will improve outcomes in patients with platinum-resistant, incurable 
SCCHN in a direct, double-blind comparison to cetuximab.


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 6 
2.1. Study Design 
This is an international, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group Phase 2 study comparing the efficacy and safety of palbociclib in combination 
with cetuximab versus cetuximab in HPV-negative, cetuximab-naïve patients with R/M 
SCCHN after failure of one platinum-containing regimen.  Approximately 120 patients will 
be randomized 1:1 between the investigational arm (Arm A: palbociclib plus cetuximab) and 
the comparator arm (Arm B: placebo plus cetuximab). Crossover between treatment arms 
will be prohibited. 
Patients will be stratified by Eastern Cooperative Oncology Group (ECOG) performance 
status (0 vs 1), and by prior use of immunotherapy (yes vs no).  
Patients randomized to Arm A (investigational arm) will receive:  
x
Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed 
by 7 days off treatment in a 28-day cycle;
in combination with 
x
Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion 
followed by 250 mg/m2 weekly infused over 60 minutes. 
Patients randomized to Arm B (comparator arm) will receive:  
x
Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in
a 28-day cycle;
in combination with 
x
Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 
mg/m2 weekly infused over 60 minutes. 
Patients will continue to receive their assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurs first.   
The importance of timely and complete disease assessments in this study cannot be 
overstated.  Disease assessments will be performed every 8 weeks (r7 days) from the date of 
randomization.  Each assessment will be performed as scheduled according to the calendar 
regardless of any dosing delay to prevent the introduction of bias into the assessment of 
efficacy.  Failure to perform any of the required disease assessments will result in the 
inability to determine disease status for that time point.  Tumor assessments will be 
performed until radiographically and/or clinically (ie, for photographed or palpable lesions) 
documented progressive disease (PD) as per RECIST v.1.1, initiation of new anticancer 
therapy, or discontinuation of patient from overall study participation (eg, death, patient's 
request, lost to follow-up), whichever occurs first.  Off schedule or incomplete disease 


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 7 
assessments have the potential to weaken the conclusion of this clinical trial and must be 
avoided wherever possible.
Patients who discontinue study treatment for reasons other than radiographically and/or 
clinically (ie, for photographed or palpable lesions) documented PD as per RECIST 
v.1.1 will continue to have tumor assessment performed during the follow-up visits every 
8 weeks (r7 days) until RECIST-defined disease progression, initiation of new anticancer 
therapy or discontinuation of patient from overall study participation (e.g., death, patient's 
request, lost to follow-up), whichever occurs first.  
Patients discontinuing the active treatment phase will enter a follow-up period during which 
survival and new anti-cancer therapy information will be collected every 2 months from the
last dose of investigational product.  The follow-up period will conclude at the time of the 
final OS analysis. 
Efficacy analyses will be performed using the local radiologist’s/investigator’s tumor 
assessments as the primary data source. 
Patients will undergo study-related safety, efficacy, and PK assessments as outlined in the 
Section 10.1 Schedule Activities.
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers assessed in tumor tissue and blood obtained prior to 
treatment for their potential predictive value in identifying patients who may benefit from 
treatment with cetuximab in combination with palbociclib or placebo. Blood and tumor 
(optional) biomarkers also assessed on-treatment provide an opportunity to investigate 
pharmacodynamics effects, and tumor specimen (optional) and blood collected upon disease 
progression (end of treatment) will be analyzed to investigate potential mechanisms of 
resistance to treatment. 
Examining and measuring the patient’s subjective experience in this study will be 
accomplished using validated health-related quality of life questionnaires. Observations will 
be documented at specified time points throughout the study, plus 1 observation after 
treatment discontinuation (to measure the impact of progressive disease on the patient’s 
quality of life). 
2.2. Study Objectives 
Primary Objective: 
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Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 8 
x
To demonstrate that the combination of palbociclib with cetuximab is superior to 
cetuximab in prolonging OS in HPV-negative, cetuximab-naïve patients with R/M 
SCCHN in whom one prior platinum-containing chemotherapy has failed.   
Secondary Objectives: 
x
To compare secondary measure of efficacy between the treatment arms; 
x
To compare safety and tolerability between the treatment arms;   
x
To compare Patient-Reported Outcome (PRO) measures between the treatment arms; 
x
To characterize the correlations between baseline biomarker (e.g., p16, Rb) 
expression in tumor tissue and clinical efficacy in both treatment arms; 
x
To characterize steady state trough concentrations for palbociclib, and trough and 
maximum concentrations for cetuximib in patients with R/M SCCHN. 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
An interim analysis will be performed when at least 50% of the required number of events 
(40 deaths) is observed.  The purpose of this interim analysis is to stop the study early for 
futility.  The formal futility boundary will be constructed using the Gamma family of 
spending function with parameter = 0.05. With 40 observed events at the interim analysis, 
the futility boundary is p-value = 0.36 (corresponding to HR = 0.9). The boundary at final 
analysis is p-value = 0.1.
The study will use an External Data Monitoring Committee (E-DMC). The E-DMC 
membership and governance are outlined in a separate charter. 
An independent third party External Data Monitoring Committee (E-DMC) will monitor the 
efficacy and safety of patients in the study according to the Charter. The E-DMC will make 
recommendation as to whether or not the trial should continue based on ongoing reviews of 
safety data.  In addition, the E-DMC will also evaluate interim efficacy data and make a 
recommendation regarding study continuation based on observed results of the study.  The 
recommendations made by the E-DMC to alter the conduct of the study will be forwarded to 
Pfizer for final decision. 
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Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 9 
The Sponsor will designate a biostatistician not affiliated with the project to prepare data for 
E-DMC review. Only if action or consultation with Health Authorities is required will other 
sponsor staff be involved in the data preparation. Clinical sites will be restricted from access 
to study results until the conclusion of the study.  
At the initiation of the trial, the trial site will be instructed on the method for breaking the 
blind.  The method will be either a manual or electronic process.  Blinding codes should only 
be broken in emergency situations for reason of patient safety.  Blinding codes may also be 
broken after a patient discontinues treatment due to disease progression, as determined by the 
treating investigator using RECIST v.1.1, but only if deemed essential to allow the 
investigator to select the patient's next treatment regimen and after discussion and agreement 
with the sponsor.  Code should not be broken in the absence of emergency situations or 
progressive disease as per RECIST v.1.1 (eg, in case of clinical deterioration, increase in 
tumor markers or any other evidence suggestive of disease progression but in the absence of 
RECIST-defined disease progression).  When the blinding code is broken, the date and 
reason for unblinding must be fully documented in source documents and entered on the 
CRF.  However, every effort should be made by the site staff to ensure that the treatment arm 
in which the unblinded patient is assigned is not communicated to any sponsor personnel or 
designee involved in the conduct of the trial.
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
The primary objective of this study is to demonstrate that the combination of palbociclib with 
cetuximab is superior to cetuximab in prolonging OS in the target population.  This study is 
designed to test the null hypothesis of equal survival between treatment arms versus the 
alternative hypothesis of improved survival in the palbociclib + cetuximab arm compared 
with the placebo + cetuximab arm. 
4.2. Sample Size Determination and Statistical Decision Rules 
Assuming a median OS of 6 months in the comparator arm, approximately 79 total events 
(deaths) are required for 1:1 randomization to have at least 80% power to detect a true hazard 
ratio of 0.6 (corresponding to a median OS of 10 month in the palbociclib arm) using a one-
sided, log-rank test at a significance level of 0.1.  One interim analysis based on OS is 
planned when at least 50% of the OS events (40 deaths) have been observed.  The purpose of 
this interim analysis is to provide an opportunity to potentially stop the study early for 
futility.  The study may be considered for early termination if the hazard ratio estimate is 
greater than 0.9.  The formal futility boundary will be constructed using the Gamma family 
of spending function with parameter = 0.05. With 40 observed events at the interim analysis, 
the futility boundary is p-value = 0.36 (corresponding to HR = 0.9). The boundary at final 
analysis is p-value = 0.1. 
Approximately 120 patients will be enrolled in about 16 months and followed for about 6 
months to observe the required number of events.  This estimation is based on the following 


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 10
assumptions on the enrollment rates: 1) 5 patients per month (on average) during the first 6 
months; 2) 10 patients per month (on average) thereafter. 
This study will be considered a positive trial if the 1-sided, log-rank test for OS in all patients 
randomized to the study is significant at level of 0.1 at the final analysis.   
5. ANALYSIS SETS 
5.1. Intent-to-Treat Population (Full Analysis Set) 
The intent-to-treat (ITT) population will include all patients who are randomized, with study 
drug assignment designated according to initial randomization, regardless of whether patients 
receive study drug or receive a different drug from that to which they were randomized.  The 
ITT population will be the primary population for evaluating all efficacy endpoints and 
patient characteristics. 
5.2. As-Treated (AT) Population (Safety Analysis Set) 
The as-treated (AT) population or safety analysis set will include all patients who receive at 
least 1 dose of study medication, with treatment assignments designated according to actual 
study treatment received. The AT population will be the primary population for evaluating 
treatment administration/compliance and safety. Efficacy and clinical benefit endpoints may 
be assessed in this population as well. 
5.3. Other Analysis Sets 
 
5.3.2. Biomarker Analysis Set 
The biomarker analysis set is defined as all patients treated with cetuximab in combination 
with placebo or palbociclib (AT population) who have at least one screening biomarker 
assessment. Analysis sets will be defined separately for 
 archival tumor tissue,
  
x
Archival Tumor Tissue Specimen - collected at screening only: AT population with 
screening assessment 
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Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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5.3.3. Patient Reported Outcome (PRO) Analysis Set 
A subset of ITT patients, who have both baseline and at least one follow-up PRO assessment 
before treatment discontinuation.
5.4. Treatment Misallocations  
x
If patients were randomized but not treated, then they will be reported under their 
randomized treatment group for efficacy analyses.  However, they are by definition 
excluded from the safety analyses. 
x
If patients were randomized but took incorrect treatment, then they will be reported 
under their randomized treatment group for efficacy analyses, but will be reported 
under the treatment they actually received for all safety analyses.  
5.5. Protocol Deviations 
All deviations will be described when they appear and relate to the statistical analyses or 
populations. 
5.5.1. Protocol Deviations Assessed Prior to Randomization 
Deviations prior to randomization are typically not allowed. Major deviations that do occur 
will be tabulated. 
5.5.2. Protocol Deviations Assessed Post Randomization  
Major deviation is defined as having been treated according to the other treatment arm.  
Patients not treated with one of the protocol treatments are excluded from safety analyses. 
Otherwise patients are not excluded from analyses due to post-randomization deviations. 
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6. ENDPOINTS AND COVARIATES 
6.1. Efficacy Endpoints 
6.1.1. Primary Endpoint  
x
Overall Survival (OS) is defined as the time from the date of randomization to the date 
of death due to any cause.  OS (in months) is calculated as (date of death − randomization 
date +1)/30.4.  For patients lacking survival data beyond the date of their last follow-up,
the OS time will be censored on the last date they were known to be alive.  Patients 
lacking survival data beyond randomization will have their OS times be censored at 
randomization.  
Following the End of Treatment visit, survival status will be collected in all patients 
every 2 months (±7 days) from the last dose of study treatment.  Information on 
subsequent anticancer therapy will also be collected. 
6.1.2. Secondary Endpoints  
x
Progression Free Survival (PFS) is defined as the time from the date of randomization
to the date of the first documentation of objective tumor progression as per RECIST v.1.1 
or death due to any cause in the absence of documented PD, whichever occurs first.  If 
tumor progression data include more than 1 date, the first date will be used.  PFS (in 
months) will be calculated as (first event date − randomization date +1)/30.4. 
Tumor assessments will be performed every 8 weeks (± 7 days) from randomization until 
radiographically and/or clinically (for photographed or palpable lesions) documented PD 
as per RECIST v.1.1, initiation of new anticancer therapy, or discontinuation of patient 
from overall study participation (e.g., death, patient's request, lost to follow up).
Imaging assessments are to be scheduled using the randomization date as the reference 
date for all time-points and are NOT to be scheduled based on the date of the previous 
imaging time-point. Patients who discontinue study treatment for reasons other than 
radiographically and/or clinically (for photographed or palpable lesions) documented 
disease progression as per RECIST definitions will continue to have tumor assessment 
performed during the follow-up visits every 8 weeks (± 7 days) until documented disease 
progression, initiation of new anticancer therapy or discontinuation of patient from 
overall study participation (e.g., death, patient's request, lost to follow-up), whichever 
occurs first. Every effort should be made to perform a last tumor assessment before 
starting a new anticancer therapy. Additional unscheduled tumor assessments may be 
performed as clinically indicated at any time. 
Patients last known to be 1) alive and 2) progression-free, are censored at the date of the 
last objective disease assessment that verified lack of disease progression (see Appendix 
10.4 for determining the date in details). In addition, 


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x
Patients with no baseline tumor assessment (including patients with an inadequate 
baseline assessment) or with no adequate post-baseline tumor assessments within 
18 weeks after the randomization date will be censored on the randomization date, 
unless the patient dies within 18 weeks of the randomization date, in which case, 
death will be an event on date of death. 
x
If a new anti-cancer treatment is started prior to progression and death, then 
censorship is at the date of the last objective disease assessment that verified lack 
of disease progression prior to the new treatment. 
x
If patients are removed from the study (withdrew the consent, lost to follow up, 
etc.) prior to progression and death, then censorship is at the date of the last 
objective disease assessment that verified lack of disease progression.
x
Patients with documentation of progression or death after an unacceptably long 
interval (≥2 consecutive assessments or > 18 weeks) since the last tumor 
assessment will be censored at the time of last objective assessment documenting 
no progression. 
x
Objective Response (OR) is defined as the overall complete response (CR) or partial 
response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 
version 1.1; Appendix 10.3.). Objective Response Rate (ORR) is defined as the 
proportion of patients with best overall response (BOR) of CR or PR relative to all 
randomized. The BOR definition is described in Appendix 10.3. Patients who do not have 
on-study radiographic tumor re-evaluation, who receive anti-tumor treatment other than 
the study medication prior to reaching a CR or PR, or who die, progress, or drop out for 
any reason prior to reaching a CR or PR will be counted as non-responders in the 
assessment of ORR.
Tumor response will be determined from tumor assessment data (where data meet the 
criteria for CR or PR as described in Appendix 10.3.).  
x
Clinical Benefit Response (CBR) is defined as the overall complete response (CR), 
partial response (PR) , or stable disease (SD) ≥24 weeks according to the Response 
Evaluation Criteria in Solid Tumors (RECIST version 1.1; Appendix 1). Clinical Benefit 
Response Rate (CBRR) is defined as the proportion of patients with CR, PR, or SD ≥24 
weeks relative to (1) all randomized patients and randomized patients with measurable 
disease at baseline. Designation of best response of SD ≥24 weeks requires the criteria to
be met at least 24 weeks after randomization. Patients who do not have on-study 
radiographic tumor re-evaluation, who receive anti-tumor treatment other than the study 
medication prior to reaching a CR or PR, a best response of SD ≥24 weeks, or who die, 
progress, or drop out for any reason prior to achieving reaching a CR or PR and a best 
response of SD ≥24 weeks will be counted as non-responders in the assessment of 
CBRR. Tumor response will be determined from tumor assessment data (where data meet 
the criteria for CR or PR and best response of SD as described in Appendix 10.3.). 
x
Duration of Response (DR) is defined as the time from the first documentation of 
objective tumor response (CR or PR) to the first documentation of disease progression or 
to death due to any cause, whichever occurs first.  If tumor progression data include more 


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than 1 date, the first date will be used.  DR will be calculated as [the date response ended 
(i.e. date of PD or death) – first CR or PR date + 1)]/30. 4.  DR will only be calculated for 
the subgroup of patients with an objective tumor response. 
Patients last known to be 1) alive and 2) progression-free, are censored at the date of the 
last objective disease assessment that verified lack of disease progression. In addition, 
x
If a new anti-cancer treatment is started prior to progression and prior to 28 days 
after discontinuation of treatment, then censorship is at the date of the last 
objective disease assessment that verified lack of disease progression prior to the 
new treatment.  
x
If patients are removed from the study (withdrew the consent, lost to follow up, 
etc.) prior to progression and death, then censorship is at the date of the last 
objective disease assessment that verified lack of disease progression.
x
Patients with documentation of progression or death after an unacceptably long 
interval (≥2 consecutive assessments or > 18 weeks) since the last tumor 
assessment will be censored at the time of last objective assessment documenting 
no progression. 
6.2. Safety Data 
Safety assessment will consist of monitoring of all AEs, including SAEs, regular monitoring 
of hematology, serum chemistry, and routine monitoring of ECGs, physical examinations, 
vital signs, and ECOG performance status.  
Overall safety profile as characterized by type, frequency, severity of adverse events as 
graded by NCI Common Toxicity Criteria for Adverse Events version 4 (NCI CTCAE 
v.4.03), timing and relationship to treatment on each arm, and laboratory abnormalities 
observed. 
Baseline tumor-related signs and symptoms will be recorded at the Cycle 1 Day 1 visit and 
then reported as AEs during the trial if they worsen in severity or increase in frequency. 
Adverse events (AEs), hematology, blood chemistry will be assessed as described in the 
Schedule of Activities of the protocol. 
Adverse events will be classified using the MedDRA classification system. The severity of 
the toxicities will be graded according to the NCI CTCAE version 4.03. For labs without 
CTCAE grade definitions, results are summarized as normal, abnormal (per Pfizer Data 
Standards (PDS)) or not done. For other AEs without specific CTCAE definitions, results are 
identified according to CTCAE “other” categories. 
Adverse events leading to death or discontinuation of trial treatment, events classified as NCI 
CTCAE v.4.03 Grade 3 or higher, trial drug related events, and serious adverse events will be 
considered with special attention. 


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The hematologic and chemistry laboratory results will be graded according to the NCI 
CTCAE v.4.03 severity grade. For parameters for which an NCI CTCAE v.4.03 scale does 
not exist, the frequency of patients with values below, within, and above the normal range for 
the local lab will be summarized. 
Patients who start treatment are assessed for toxicities up to 28 days after the final dose of 
treatment or start of new treatment (whichever comes first). Toxicities observed beyond 28 
days and recorded in the database per Sponsor's agreement will be included in the 
summaries. 
6.2.1. Treatment Emergent Adverse Event 
An adverse event is considered treatment emergent if: 
x
The event occurs for the first time after the start of study treatment and before 28 days 
after final dose of study treatment and was not seen prior to the start of treatment or 
x
The event was seen prior to the start of treatment but increased in NCI CTCAE v.4.0
grade during study treatment. 
x
Disease progression is not considered a treatment emergent adverse event unless the 
patient dies of disease prior to 28 days after discontinuation of treatment. 
6.2.2. Treatment Related Adverse Event 
Adverse events defined as treatment emergent adverse events with cause possibly, probably 
or definitely related to treatment as judged by the investigator are defined as treatment related 
adverse events. Events that are continuation of baseline abnormalities are not considered 
treatment related unless there is an increase in grade, or if there is an increase following a 
decrease, and the increase is judged by the investigator to be caused by the treatment. 
6.2.3. Laboratory Safety Assessments 
Laboratory assessment will be assigned to cycles based on the collection date of the sample 
relative to the start dates of cycles from the study drug administration as described in the 
Schedule of Activities table in Appendix 10.1. 
Baseline evaluations for laboratory are those collected 
x
Within 28 days prior to or on first day of study drug and 
x
If there is more than one baseline evaluation, closest to but any time prior to the 1st
dosing on the first day of study treatment. 
Blood tests will include the following: 
Hematology
Chemistry
Hemoglobin
ALT
WBC
AST
Platelets
Alkaline Phosphatase
Absolute Neutrophils
Sodium


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Absolute Lymphocytes
Potassium
Magnesium
Coagulation
Chloride
PT or INR
Total Calcium
PTT
Total Bilirubin *
BUN or Urea
Creatinine
Uric Acid
Glucose (fasted)
HbA1c
Albumin
Phosphorus or Phosphate
*For potential Hy’s law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/INR, and alkaline phosphastase. 
For all patients, 8 weeks after the completion of therapy, blood chemistry panel consisting of 
magnesium, total calcium, and potassium must be checked.  If abnormalities are observed, an 
ECG can be performed at the discretion of the investigator to check QTc. 
6.2.4. Electrocardiogram (ECG) 
All ECGs will be performed using a 12-lead (with a 10-second rhythm strip) tracing.  ECG 
measurements will include PR interval, QT interval, RR interval, and QRS complex.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  
ECG interval readings by the ECG recorder’s algorithm will be read and interpreted at the 
investigational site for eligibility determination and patient safety monitoring and 
documentation stored in the source documents.  
Triplicate ECGs will be performed for all patients. 
x
All ECGs should be obtained after a fast of at least 1 hour. When scheduled at the 
same nominal time/visit, triplicate ECGs should be collected prior to any blood draws 
for PK, biomarkers, or safety labs and prior to placement of the IV line for cetuximab 
administration. 
x
Triplicate ECGs will be obtained for safety monitoring at Screening, and 0 hour 
(palbociclib pre-dose) on C1D1, C1D15 and C2D15, then on Day 1 of Cycles 4, 7, 
and 10.  ECGs will be obtained at the time of End of Treatment or Withdrawal.  
ECGs beyond Cycle 10 will be performed as clinically indicated. 
Additional ECGs may be performed as clinically indicated at any time. 
For the purpose of the study, triplicate ECGs are defined as three consecutive ECGs 
performed approximately 2 minutes apart but within 10 minutes for all 3 ECGs at the 
protocol specified timepoints (see Section 10.1. Schedule of Activities for details) to 
determine the mean QTc interval.   


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6.2.5. Other Safety Assessment 
A full physical examination including an examination of all major body systems (including 
head, ears, eyes, nose, mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and 
musculoskeletal), height (at screening only), weight, blood pressure and pulse rate which 
may be performed by a physician, registered nurse or other qualified health care provider, 
will be required at screening, and Day 1 of Cycles 1 and 2.  
Symptom directed physical examinations, blood pressure and pulse rate will be performed at 
subsequent visits. Performance Status: The Eastern Cooperative Oncology Group (ECOG) 
performance status scale will be used. 
 
  
  
  
  
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6.3.3. Patient Reported Outcome Endpoints  
Patient reported outcomes of functioning , symptoms and global QOL will be assessed using 
the EORTC-QLQ-C30, and EORTC-QLQ-H&N 35 instruments.  
Patients will complete each instrument at pre-dose on Day 1 of Cycles 1-3, then on Day 1 of 
every other subsequent Cycle starting with Cycle 5 (e.g., cycles 5, 7, 9, etc.), and then at the 
End of Treatment visit. This schedule is based on the schedule for the assessment of clinical 
activity.  Four weeks after discontinuation of study treatment due to progressive disease, 
patients, including patients starting post-study anticancer therapy, will be completing the 
questionnaires at the Follow-up Visit.
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6.3.3.1. European Organisation for Research and Treatment of Cancer Quality of Life 
Instrument (EORTC QLQ-C30) 
The EORTC QLQ C30 is a 30 item questionnaire composed of five multi item functional 
subscales (physical, role, cognitive emotional, and social functioning), three multi item 
symptom scales (fatigue, nausea/vomiting, and pain), a global health/quality of life (QOL) 
subscale, and six single items assessing other cancer related symptoms (dyspnea, sleep 
disturbance, appetite, diarrhea, constipation, and the financial impact of cancer).  The 
questionnaire employs 28 four point Likert scales with responses from “not at all” to “very 
much” and two 7 point Likert scales for global health and overall QOL. The scores are 
transformed to a 0 to 100 scale. For functional and global QOL scales, higher scores 
represent a better level of functioning/QOL while for symptom scales, a higher score 
represents more severe symptoms. 
6.3.3.2. European Organisation for Research and Treatment of Cancer Head and Neck 
Module 35 (EORTC QLQ-H&N35) 
The EORTC QLQ-H&N35 is designed to be used together with the core QLQ-C30. The time 
frame of the module is ‘‘during the past week,’’ and the format is similar to that of the core 
questionnaire. Items hn 1 to hn30 are scored on four-point Likert-type categorical scales 
(‘‘not at all,’’ ‘‘a little,’’ ‘‘quite a bit,’’ ‘‘very much’’). Items hn31 to hn35 have a ‘‘no/yes’’ 
response format. The scores are transformed into 0-to-100 scales, with a high score implying 
a high level of symptoms or problems, in the same way as scoring for symptom scales and 
single items of the QLQ-C30. 
6.4. Covariates and Stratification Factors 
6.4.1. Covariates  
The potential influences of baseline patient characteristics such as age, gender, ethnic origin, 
ECOG performance status, geographical region, selected biomarkers, and stratification 
factors on the primary endpoint OS, PFS, and OR endpoints may be evaluated. 
6.4.2. Stratification Factors  
x
Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1) 
x
Prior use of immunotherapy (yes vs. no) 
7. HANDLING OF MISSING VALUES 
7.1. Missing Dates 
In compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (e.g., date of onset cannot be prior to day one 
date).  In this case, the date resulting in 1 day duration will be used. If the day of the month 
and the month is missing for any date used in a calculation, January 1 will be used to replace 
the missing date. 


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Missing dates for adverse events will be imputed based on the similar principle. 
x
For the start date, if the day of the month is missing, the 1st day of the month will be 
used to replace the missing date. If both day and month are missing, January 1 of the 
non-missing year will be used to replace the missing date. If the first dose date is later 
than this imputed date, then impute the start date again to the first dose date. 
x
For the stop date, if the day of the month is missing, the last day of the month will be 
used to replace the missing date. If both day and month are missing, December 31 of 
the non-missing year will be used to replace the missing date. 
If the start date is missing for an AE, the AE is considered to be treatment emergent unless 
the collection date is prior to the treatment start date. 
7.2. Missing Tumor Assessments 
If baseline tumor assessment is inadequate the patient cannot be assessed for response. 
Inadequate baseline assessment may include  
x
Not all required baseline assessments were done 
x
Assessments were done outside the required window  
x
Measurements were not provided for one or more target lesions 
x
One or more lesions designated as target were not measurable. 
If measurements for one or more target lesions are missing for an evaluation and disease does 
not qualify as progression (or symptomatic deterioration if applicable), the objective status 
for that evaluation is Indeterminate. 
If non-target disease was not assessed, then objective status cannot be a CR even if all target 
disease has disappeared.  Otherwise, missing non-target disease assessments do not 
necessarily affect response determination.  Such cases will be reviewed carefully. 
If a lesion measurement is missing because it is documented as too small to measure, the 
value 5 mm will be assigned and objective status calculated accordingly.   
In the assessment of OR, patients who do not have on study radiographic tumor re-
evaluations will be counted as non-responders. 
7.3. Missing Data in PFS Derivation 
PFS cannot be assessed in patients with inadequate baseline tumor assessment. PFS cannot 
be assessed in patients who have no on-study assessments unless death occurs prior to the 
first planned assessment time.  
If a substantial number of patients have questionable failure or censorship dates for either 
PFS definition (such as progression or death not documented until after multiple missing 


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assessments) scenarios such as best case (failure at time of documentation) and worst case 
(progression at earliest possible planned assessment date) will be investigated.   
For PFS analysis, no values will be imputed for missing data.  For time to event endpoints, 
non-event observations will be censored as defined in Section 6.   
7.4. Missing QTc Data 
For QTc analysis, no values will be imputed for missing data except for averaging of 
triplicate measurements. If one or two of the triplicate measurements for an ECG parameter 
are missed, the average of the remaining two measurements or the single measurement can 
be used in the analyses. If all triplicate measurements are missing at a time point for an ECG 
parameter, no values will be imputed for this time point and no analyses related to this time 
point will be performed.  If the triplicate is not good because of an artifact, then if the 
triplicate is repeated within about r 15 minutes can be used at that nominal time. Patients 
who have data on other days or unscheduled ECGs but not at the times of the formal 
statistical analysis will be included in the categorical tables but not the statistical analyses. 
7.5. Missing Patient Reported Outcome Data 
For the EORTC-QLQ-C30 and EORTC-QLQ-H&N35, in cases where two answers are given 
to one item, the more severe answer will be counted. If at least half of the constituent items 
for the multi-item functional or symptom scale have been answered, then the score for that 
scale may be pro-rated based on the non-missing items. For subsequent analysis purposes, 
missing items will be considered missing; they will not be imputed. 
 
 
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8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods  
8.1.1. Analyses for Time-to-Event Data 
Time-to-event endpoints between the 2 treatment arms will be compared with a 1-sided log-
rank test and/or a 1-sided stratified log-rank test at the D=0.1 overall significance level. 
Hazard ratios and 2-sided 80% and 95% confidence intervals will be estimated using Cox 
proportional hazards regression.
Cox proportional hazard models will also be used to explore the potential influences of the 
baseline stratification factors (as listed in Section 6.4.2) on time-to-event endpoints. In 
addition, potential influences of baseline patient characteristics such as age, gender, race, 
ethnic origin, geographical region, and selected biomarkers on the endpoints may be 
evaluated. A backward selection process (with treatment in the model) will be applied to 
these variables to identify the final set of relevant factors. Treatment-by-factor interactions 
will be explored only for the set of factors included in the final model. The estimated hazard 
ratio and 2-sided 80% and 95% confidence intervals will be provided. Additionally for each 
treatment arm, the median event time and a 2-sided 95% confidence intervals will be 
provided for each level of stratification factors or baseline characteristics.  
Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate.  Median event times and 2-sided 95% confidence intervals for 
each median will be provided.
The survival probability at 4, 6, and 12 months will be estimated using the Kaplan-Meier 
method and a 2-sided 95% confidence interval for the log [-log(X-year survival probability)] 
will be calculated using a normal approximation and then back transformed to give a
confidence interval for the survival probability at 4, 6, and 12 month.
Since patients in both treatment arms may receive other available treatments after disease 
progression, the treatment effect on overall survival may not be able to estimate properly by 
above defined methods because of these confounding factors. Therefore, the proper testing 
statistics such as Wilcoxon test and methods like Rank-Preserving Structural Failure Time 
Model (RPSFTM) proposed by Robins and Tsiatis will be applied to the overall survival 
analysis. 
8.1.2. Analyses of Binary Data 
The rates of binary endpoints for the two treatments will be tested with a 1-sided significance 
level of 0.1 using an exact test. The odds ratio and its 80% and 95% confidence intervals will 
be calculated. In addition, point estimates of the rates for each treatment arm will be provided 
along with the corresponding exact 2-sided 95% confidence intervals using the exact method 
based on Clopper-Pearson method, while the point estimate of the difference of the rates 
between treatment arm will be provided along with corresponding approximate 2-sided 95% 
confidence intervals based on normal distribution.  


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8.1.3. Analyses of Continuous Data 
Descriptive statistics, including the n, mean, standard deviation, median, minimum, and 
maximum values, will be provided for continuous endpoints. Descriptive statistics for 
biomarkers will include %CV. 
8.1.4. Analyses for Categorical Data  
The number and percentage of patients in each category will be provided for categorical 
variables.   
8.1.5. Analyses for QTc Data  
8.1.5.1. Derived Analysis Variables 
All ECGs will be recorded in triplicate i.e. three ECGs taken 2 minutes apart. ECG 
assessments reported by the site will include the following parameters: 
ECG Parameter
Units
Abbreviation
QTc, Fridericia’s correction
msec
QTcF
QTc, Bazett’s correction
msec
QTcB
QT Interval
msec
QT
Heart Rate
bpm
HR
PR Interval
msec
PR
RR Interval
msec
RR
QRS Complex
msec
QRS
The following variables will be derived as follows: 
ECG Parameter
Units
Abbrev.
Derivation
QTc, study specific 
correction
msec
QTcS
= QT/(RR) S (derivation of S is 
given in section 8.1.5.2.)
Averaging of triplicate measurements:  
After the above variables have been derived within each patient and scheduled time-point, 
each ECG parameter (including QTcF, QTcB, QTcS, QT, HR, PR, RR, QRS) should each be 
averaged as follows:  (1st measurement + 2nd measurement + 3rd measurement) / 3.  All 
summary statistics, analyses and figures will be based on the triplicate averaged data. 
8.1.5.2. Derivation of Study Specific QT Correction Factor 
The study specific QT correction factor (ICH E14 Step 4, May 12, 2005) will be derived.  
The dataset will consist of Screening and baseline assessments of QT and RR.
Prior to estimating the regression, QT and RR will be transformed by the natural logarithm to 
Ln(QT) and Ln(RR), respectively.  Ln (RR) will be treated in the regression as the 


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explanatory variable with Ln (QT) as the response variable.  The regression equation will be 
as follows: 
Ln(QT) = Intercept + S u Ln(RR) + Error 
Where  S = slope of the regression line. 
Once (S) is estimated, it will be used to derive the study specific QT correction, QTcS. 
8.1.5.3. Assessment of QT Correction Methods   
This assessment will utilize only Screening and baseline triplicate averaged data (“Study 
drug-free” ECG data).
The relationship between QT/QTc and RR and the adequacy of each of the 3 QT correction 
methods will be assessed by the following scatterplots (see Figure 1): 
x
QT, QTcF, QTcB, and QTcS vs. RR  
Interpretation of the scatterplots should give the following information: 
x
Variability of the QT/QTc relative to changing RR 
x
Slope or lack of slope and pattern to assess adequacy of QT correction method 
x
Apparent patterns in the data 
Figure 1. A Sample scatterplot of relationship between QT/QTc and RR
8.1.5.4. Change from Baseline Definition 
The change from baseline calculations for ECG measurements (abbreviated as “change”) is
derived from the triplicate averaged measurements.  The baseline ECG assessment is defined 
as the triplicate ECG assessment taken pre-dose on Cycle 1 Day 1, or the most recent 
triplicate ECG assessment reported prior to the first administration of study drug.  Change 
from baseline is defined as a patient’s parameter value at a particular time-point minus the 


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appropriately matched baseline value (value - baseline value). Change from baseline 
calculations should only use post-dose ECG measurements. 
8.1.5.5. Outlier Analysis 
QT/QTc outlier values will be summarized and tabulated by the following CTCAE grade 
v.4.03.
Grade
1
2
3
4
5
Prolonged 
QTc 
interval
QTc  450 –
480 msec
QTc 481 –
500 msec
QTc t501
msec on at 
least two 
separate 
ECGs
QTc t501 or >60 msec
change from baseline 
and Torsade de pointes 
or polymorphic 
ventricular tachycardia 
or signs/symptoms of 
serious arrhythmia
Death
The change from baseline will summarize occurrences of shift by t 1 grade by CTC. 
Individual QT and QTc values t501 msec from each ECG within a triplicate will be flagged 
in data listings. 
In addition, the maximum QTc value for each patient can be categorized and summarized in 
the following cut-offs.  All post dose QTc interval data should be used in determining the 
maximum for a patient, including all scheduled and unscheduled ECG’s. 
Absolute QTc interval 
prolongation
QTc < 450 msec
450 msec ≤QTc ≤ 480 msec
481 msec ≤QTc ≤ 500 msec
QTc t501 msec
The maximum increase from baseline QTc value for each patient by treatment will be 
categorized and summarized as well.  For reporting the maximum increase QTc value the 
following categories: <30 msec, 30-59 msec and ≥60 msec will be used. 
8.2. Statistical Analyses  
All efficacy analyses will be conducted on intent-to-treat (ITT) population. Some efficacy 
analyses will also be performed on the AT populations, if appropriate. All analyses will be 
performed by using SAS® Version 9.4 or higher.  
The analyses of endpoints dependent on disease assessments (PFS, OR, and DR) will be 
based on investigator assessments of disease response and progression. 


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All primary and secondary analyses will be tested at a significance level of 0.1 (1-sided test). 
No adjustments are planned for multiple testing/comparisons in the secondary hypothesis 
tests. 
8.2.1. Primary Efficacy Analysis 
OS will be summarized in the ITT population using the Kaplan-Meier methods and displayed 
graphically where appropriate.  The median event time and 2-sided 95% and 80% confidence 
intervals for the median will be provided. A stratified (by ECOG) log-rank test will be used 
to compare OS between two treatment arms and the hazard ratio and its 80% and 95%
confidence intervals will be estimated.
The survival probabilities at 4, 6, and 12 months will be provided with their 95% confidence 
intervals. 
The log-rank (unstratified) test (1-sided, D=0.1) will be used to evaluate the primary efficacy 
endpoint, OS, in the ITT population. The same analysis may be used in AT populations.
Since patients in both treatment arms may receive other available treatments after disease 
progression, the treatment effect on overall survival may not be able to estimate properly by 
above defined methods because of these confounding factors. Therefore, the proper testing 
statistics such as a Wilcoxon test and RPSFTM may be applied to the overall survival 
analysis if the OS data cannot be evaluated properly by the log-rank test because of 
subsequent treatments after disease progression. 
8.2.2. Secondary Analyses 
PFS based on the assessment of investigator will be summarized in the ITT population using 
the Kaplan-Meier method and displayed graphically where appropriate. The median event 
time and corresponding 2-sided 95% confidence interval for the median will be provided for 
PFS.  The hazard ratio and its 80% and 95% confidence intervals will be estimated. A
stratified (by ECOG) log-rank test and a unstratified log-rank test (1-sided, D=0.1) will be 
used to compare PFS between the two treatment arms. 
The number and proportion of patients achieving objective response (CR or PR) will be 
summarized in the ITT population along with the corresponding exact 2-sided 95% 
confidence interval calculated using a method based on Clopper-Pearson method. The CMH 
test stratified by ECOG and exact test will be used to compare ORR between two treatment 
arms. 
The number and proportion of patients achieving disease control response (CR or PR or SD)
will be summarized in the ITT population along with the corresponding exact 2-sided 95% 
confidence interval calculated using a method based on Clopper-Pearson method. The CMH 
test stratified by ECOG and exact test will be used to compare CBR between two treatment 
arms. 
The number and proportion of patients achieving clinical benefit response (CR or PR or 
SD≥24 weeks) will be summarized in the ITT population along with the corresponding exact 


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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2-sided 95% confidence interval calculated using a method based on Clopper-Pearson 
method. The CMH test stratified by ECOG and exact test will be used to compare CBR 
between two treatment arms. 
DR will be summarized using the Kaplan-Meier methods and displayed graphically where 
appropriate.  DR will be calculated for the subgroup of patients achieving objective disease 
response (CR or PR). The median event time and 2-sided 95% confidence interval for the 
median will be provided.  
8.2.3. Sensitivity Analyses for PFS  
The efficacy analysis on PFS is based on well-documented and verifiable progression events 
and deaths due to any cause. Other data are censored on the day following the date of the last 
tumor assessment documenting absence of progressive disease and death. In addition, several 
sensitivity analyses on the PFS will be performed in determining whether the main PFS 
analysis is robust.   
Influence of additional anti-cancer therapy prior to disease progression or death -A
sensitivity analysis will be performed by following patients until PD after discontinuation of 
the study treatment regardless the initiation of additional anti-cancer therapies. PFS data will 
be censored on the day of the last tumor assessment documenting absence of progressive 
disease or death for patients who  
x
Are removed from the study prior to documentation of objective tumor progression;
or 
x
Remaining on study without PD or death at the time of the analysis.  
Influence of Disease Assessment Scheduling - A sensitivity analysis will be performed to 
investigate whether deviations in disease assessment scheduling influenced the outcome of 
the primary endpoint PFS.  If disease progression is documented between 2 scheduled tumor 
assessments, then the date of progression will be assigned to the earlier scheduled tumor 
assessment.  In the event of death, the date of the endpoint will not be adjusted.  Handling of 
missed disease assessments will be similar to that in the primary analysis except that any 
missed assessment will result in censoring. 
Influence of Censoring for Patients Who Discontinued from Study due to Adverse 
Event or Systemic Deterioration – A sensitivity analysis will be performed to investigate 
whether the censoring for patients discontinued without PD due to adverse event or systemic 
deterioration of health. In this analysis, the patients who are censored in primary analysis will 
be counted as events.  
In addition, the potential influences of the stratification factors (as listed in Section 6.4.2) and 
baseline patient characteristics such as age, gender, ethnic origin, ECOG performance status, 
geographical region, and selected biomarkers on the primary PFS endpoint will be evaluated. 


Protocol A5481044  
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8.2.4. Standard Analyses  
Descriptive statistics will be used to summarize study conduct and patient disposition, 
baseline characteristics, and treatment administration/compliance.   
x
Study Conduct and Patient Disposition - an accounting of the study patients will be 
tabulated including randomized (per stratification factors), treated, accrual by study 
center, assessed for AEs, laboratory data, biomarkers, PK, and QTc, etc.  Patients not 
meeting the eligibility criteria will be identified.  Patients not completing the study will 
be listed along with the reason for their premature discontinuation.  Reasons for 
premature discontinuation will be summarized.  Randomization errors and stratification 
errors will be described. 
x
Baseline Characteristics - patient characteristics such as patient age, height, weight, 
gender, race, ethnicity, ECOG performance status, primary diagnosis, ER and HER2 
status, prior therapy (radiotherapy, surgery, systemic therapy), baseline disease site, prior 
medication, medical history, and signs and symptoms at study entry will be summarized 
in frequency tables, and descriptive statistics will be provided for quantitative variables.  
x
Treatment Administration and Compliance
x
Extent of Treatment 
The extent of treatment will be summarized as follows: 
 
x
The number and % of patients on treatment and off for each reason 
x
Treatment assigned vs. actual received  
x
The number and percent of patients beginning 1, 2, 3, 4, 5+ cycles of either study 
drug  
x
The number of cycles started (median, minimum, maximum) will be reported 
(overall and by study treatment).    
x
Duration of treatment (overall and by study treatment) 
x
Cumulative dose and relative dose intensity (see Appendix 10.6 for details) 
(overall and by cycle; by study treatment)  
x
Treatment Delays and Dose Modifications 
Treatment delays and dose modifications of study treatments will be summarized as 
follows including number and percent (see Appendix 10.6 for details): 
x
The number of patients with at least one palbociclib or cetuximab dose reduction 
and the number of patients with at least one palbociclib or cetuximab dose
omission at any time during drug administration will be reported. 
x
The number of patients with at least one palbociclib or cetuximab dose reduction 
due to an adverse event will be reported. 
x
The number of patients with at least one palbociclib dose (i.e. start of following 
cycle is delayed) or cetuximab dose delay (i.e. start of following dose is delayed) 
and percentage due to each reason for the delay will be reported  


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 30
x
Concomitant medications and Non-drug treatments
Concomitant and non-drug treatments refer to all drug and non-drug treatments taken 
while on active treatment (during the effective duration of study treatment), whether 
or not they are recorded at baseline (i.e. have stop day greater than or equal to day 1 
relative to first dose of study drug). Concomitant medication will be summarized in 
frequency tables by treatment. 
x
Follow-Up Therapy  
Follow-up cancer therapy will be summarized by treatment as patients with number 
of regimens (0, 1, 2, t3), and patients with particular agents. 
8.2.5. Safety Analyses 
Listings of AE, SAE, death, lab data, vital signs, and physical examinations will be provided 
according to reporting standard. 
8.2.5.1. Adverse Events 
All patients treated with at least one dose of study treatment (i.e. palbociclib/Placebo or 
cetuximab) will be included in all the safety analyses.  
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v.4.03 whenever possible (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for selected events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates this exploratory analysis. 
Adverse events will be summarized by treatment and by the frequency of patients 
experiencing treatment emergent adverse events corresponding to body systems and 
MedDRA preferred term.  Adverse events will be graded by worst NCI CTCAE v.4.03 grade. 
Adverse events will be summarized by cycle and by relatedness to trial treatment. Detailed 
information collected for each AE will include a description of the event, duration, whether 
the AE was serious, intensity, relationship to study drug, action taken, and clinical outcome. 
Emphasis in the analysis will be placed on AEs classified as treatment emergent. 
Adverse events leading to death or discontinuation of trial treatment, events classified as NCI 
CTCAE v.4.03s Grade 3 or higher, trial drug related events, and serious adverse events will 
be considered with special attention. 


Protocol A5481044  
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The percentage of patients with an event will be calculated using the number of patients in 
the as-treated population as the denominator. The denominator for summary tables for each 
laboratory parameter will be all patients in the as-treated population with at least one 
evaluable cycle for that parameter. 
x
For Tier-1 events, the MedDRA preferred term, treatment arm, n (%) for each 
MedDRA preferred term per arm, risk difference, 95% confidence interval and P-
values for the risk difference will be provided. Graphical format may be presented as 
well. Presented in descending p-value order. 
x
For Tier-2 events, the MedDRA preferred term, treatment arm, n (%) for each 
MedDRA preferred term per treatment arm, risk difference and 95% confidence 
intervals for the risk difference will be provided in tabular format. Table by AE for
All Grade and for Grade 3/4/5 will be provided. Graphical format may be presented 
as well. Presented in descending risk difference order. 
x
Tier-3 events will be presented by observed event proportions. The following will be 
provided:
o
Incidence and grades of treatment emergent (all causality, preferred term, and 
by System Organ Class) AEs for all cycles combined. 
o
Incidence and grades of treatment emergent (all causality, preferred term) AEs 
for all cycles combined in descending frequency order. 
o
Incidence and grades of treatment emergent (treatment related, preferred term 
and by System Organ Class) AEs for all cycles combined. 
o
Incidence and grades of treatment emergent (treatment related, preferred term) 
AEs for all cycles combined in descending frequency order. 
x
Disease progression will not be included 
x
There will be no adjustment for multiplicity 
The following summaries of treatment emergent adverse events will also be provided by arm: 
x
Discontinuations Due to Adverse Events including causality: all cause, treatment 
related, including relationship to specific study treatment of cetuximab, palbociclib, 
and placebo 
x
Temporary Discontinuations or Dose Reductions Due to Adverse Events including
causality and relationship to specific study treatment of cetuximab, palbociclib, and 
placebo 
x
Treatment-Emergent Adverse Events (All Causality, and Treatment Related) 
including the number of patients evaluable for adverse events, total number of 


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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adverse events (counting each unique preferred term across all patients), number of 
patients with serious adverse events, number of patients with Grades 3 and 4 adverse 
events, number of patients with Grade 5 adverse events, and number with dose 
reductions or temporary discontinuations due to adverse events 
x
Treatment-Emergent Adverse Events by MedDRA System Organ Class, Preferred 
Term and Maximum NCI CTCAE v.4.03 Grade (All Causality, and Treatment 
related) 
x
Treatment-Emergent Adverse Events by MedDRA Preferred Term sorted by 
Descending Order of AE Frequency (All Causality, and Treatment related) 
x
Treatment-Emergent Adverse Events by Preferred Term – Grade 3/4/5 events with 
number of patients experienced Grade 3-5 AEs and total number of Grade 3-5 AEs, 
sorted by Descending Order of AE Frequency (All Causality, and Treatment Related) 
A summary of Serious Adverse Events and listing of deaths reported as serious adverse 
events will be provided. 
8.2.5.2. Laboratory abnormalities 
Hematologic, chemistry and urinalysis laboratory data will be summarized by cycle. The 
hematologic and chemistry laboratory results will be graded according to the NCI CTCAE 
v.4.03 severity grade. For parameters for which an NCI CTCAE v.4.03 scale does not exist, 
the frequency of patients with values below, within, and above the normal range for the local 
lab will be summarized. Each patient will be summarized by the worst severity grade 
observed for a particular laboratory parameter. This will be provided for all cycles as well as 
by cycles. 
8.2.6. QTc Analyses 
All ECGs obtained during the study will be evaluated for safety. The triplicate data will be 
averaged and all summary statistics and data presentations will use the triplicate averaged 
data. Any data obtained from ECGs repeated for safety reasons after the nominal time-points 
will not be averaged along with the preceding triplicates. 
For all patients in the safety analysis population, individual change in QTc (QTcF, QTcB, 
QTc S) will be calculated for each nominal post-baseline time point. These individual 
changes will be summarized using descriptive statistics. 
For all patients in the safety analysis population, categorical analysis of the 
QTcF/QTcB/QTcS data will be conducted and summarized as follows: 
1. QT/QTc outlier values will be summarized and tabulated by the following CTCAE grade 
v.4.03 according to 8.1.6.7.
2. The change from baseline will summarize occurrences of shift by t 1 grade by CTC.


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 33
3.
Individual QT and QTc values t501 msec from each ECG within a triplicate will be 
flagged in data listings.
4. The number of and percentage patients with maximum post-dose QTcF/QTcB/QTcS
(<450, 450-480, 481-500, and ≥501 ms), including all scheduled and unscheduled ECG’s. 
5. The number and percentage of patients with maximum increase from baseline in 
QTcF/QTcB/QTcS (<30, 30- 60, and > 60 ms), including all scheduled and unscheduled 
ECG’s. 
6. PR changes from baseline ≥ 50% if absolute baseline value was < 200 ms, and ≥ 25% if 
absolute baseline value was > 200 ms. 
7. QRS changes from baseline ≥ 50% if absolute baseline value was < 100 ms, and ≥ 25% if 
absolute baseline value was > 100 ms.
8. The number and percentage of individuals with abnormal ECG findings.
 
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Protocol A5481044  
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8.2.8. Biomarkers Analyses 
Biomarkers will be assessed separately from 
 archival tumor tissue 
 
In each case, summaries of baseline levels, ratio to baseline (where 
appropriate), expression and mutation will be reported, by treatment group and combined. 
For continuous variables, summary statistics may include the mean, ratio to baseline, 
standard deviation, 25th median, and 75th quartile, % CV, and minimum/maximum levels of 
biomarker measures; for categorical variables, summary may include number and percentage, 
odds ratio as appropriate.   Statistical analyses comparing treatment groups will be performed 
using the appropriate method (exact Wilcoxon Rank Sum test for continuous variables, 
Fisher’s exact test or Wilcoxon signed rank for discrete variables.)  Cox proportional hazard 
methods for biomarkers included as covariates to predict PFS/OS, or K-M analysis split ≥or 
< median biomarker value (for continuous biomarkers) or presence/absence (for discrete 
biomarkers) may be performed, following the methods described in Section 8.2.1.  
For p16 and Rb expression in the palbociclib and cetuximab treatment group, the relationship 
of the biomarkers (individually) with PFS and OS will be explored using graphical methods 
such as box plots, at baseline. 
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Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 35
  
  
  
8.2.9. Patient Reported Outcomes Analyses 
The primary analysis set for the PRO endpoints will be the ITT population. Change from 
baseline analyses will be performed on the PRO evaluable population as appropriate. 
The PRO analysis endpoints will be based on the instruments QLQ-C30 and QLQ-H&N35.
For each treatment group and at each time point, the number and percentage of patients who 
completed these instruments will be summarized, as will the reasons for non-completion of 
these measures.  An instrument is considered completed if at least one item was answered by 
the patient.  
For each endpoint a completion status table will be provided showing the numbers and 
percentages of patients at each visit and the numbers and percentages of patients at that visit 
who completed none, at least one, or all of the items for that endpoint. Post treatment 
discontinuation observation will be excluded from primary analyses set and only included in 
pre-specified sensitivities or post hoc analyses. 
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Protocol A5481044  
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Page 36
8.2.9.1. EORTC QLQ-C30 
This questionnaire contains 30 questions organized into 5 multi-item functional scales, 3 
multi-item symptom scales, a global  quality of life scale, and 6 single item symptom scales.  
For each of the 15 scales, the results will be summarized using means (and standard 
deviation), 95% confidence interval, and medians (and range) for each treatment group at 
each time point.  This will be done based on the observed values as well as changes from 
baseline where both within group and between group differences will be displayed.   
For each of the 15 scales, statistical comparison between the two treatment groups will be 
based on a longitudinal repeated measures analysis using a mixed effects model for observed 
scores and change from baseline scores controlling for baseline.  The variables in the model 
will be treatment, time, treatment-by-time, with baseline used as a covariate.  Parameter 
estimates will be based on a restricted maximum likelihood method and an unstructured 
covariance matrix will be used. Should convergence not be obtained with the unstructured 
covariance matrix, other structures can be considered.  No adjustments for multiple 
comparisons will be made. 
For each of the 15 scales, a graphical display of means over time as well as mean changes 
from baseline over time will also be provided. 
8.2.9.2. EORTC QLQ-H&N35 
This questionnaire contains 35 questions organized into 7 multi-item scales and 11 single-
item scales.  As with C30, the analysis of the H&N35 scales will consist of descriptive 
statistics on observed and changes from baseline scores, and a between treatment comparison 
using a longitudinal mixed effects model. Also, as with C30, graphical displays of means and 
changes from baseline over time will also be provided for each H&N35 scale. 
 
  
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Protocol A5481044  
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Page 37
8.3. Summary of Key Clinical Efficacy Analyses  
Type of Analysis
Endpoint
Analysis Set
Statistical Method 
Primary
OS
ITT
(See 8.2.1)
Stratified log-rank test (stratified by ECOG) (1-
sided, D=0.1),
K-M method (median and 95% CI)
HR, 80% and 95% CI from the Cox model
Secondary
OS
ITT
(See 8.2.1)
Unstratified Log-rank test (1-sided, D=0.1),
K-M method (median and 95% CI)
HR, 80% and 95% CI from the Cox model
Wilcoxon test
RPSFT method
Survival probability at 4, 6, and 12 months
Secondary
OS
AT 
(See 8.2.1)
Unstratified Log-rank test (1-sided, D=0.1),
K-M method (median and 95% CI)
HR, 80% and 95% CI from the Cox model
Secondary
PFS
ITT
Investigator 
assessment
(See 8.2.2)
Stratified log-rank test (stratified by ECOG) and 
Unstratified Log-rank test (1-sided, D=0.1),
K-M method (median and 95% CI)
HR, 80% and 95% CI from the Cox model
Secondary
Sensitivity analysis
1- 3
PFS
ITT
Investigator
assessment
(See 8.2.3)
Unstratified Log-rank test 
K-M method (median and 95% CI)
HR, 80% and 95% CI from the Cox model
Secondary 
OR
ITT
Investigator 
assessment
(See 8.2.2)
CMH Stratified by ECOG and Exact test 
Exact CI based on Clopper-Pearson method (95% 
CI) 
Secondary 
CBR
ITT
Investigator 
assessment
(See 8.2.2)
CMH Stratified by ECOG and Exact test 
Exact CI based on Clopper-Pearson method (95% 
CI) 
Secondary
DR
ITT patients with 
a CR or PR
Investigator 
assessments 
(See 8.2.2)
K-M method (median and 95% CI)
Abbreviations: 
ITT: intent-to-treat; At: as-treated 
DR: duration of response; OR: objective response; OS: overall survival; PFS: progression-free survival.


Protocol A5481044  
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9. REFERENCES  
1.
Brookmeyer R, Crowley JJ.  A confidence interval for the median survival time.  Biometrics 
1982; 38:29-41. 
2.
Cox DR. Regression models and life-tables (with discussion). Journal of the Royal Statistical 
Society, Series B 1972; 34:187-220.
3.
DeMets D, Lan KKG. Interim analysis: the Alpha Spending function approach. Statistics in 
Medicine 1994; 13:1341-1352. 
4.
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumors: Revised RECIST guideline version 1.1. Eur J 
Can 45: 228-47, 2009. 
5.
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc 
1958; 53:457-481. 
6.
Robins JM, and Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics. - Theory and Methods. 
1991; 20:2609-2631.
7.
Pampallona S and Tsiatis AA, Group sequential designs for one-sided and two-sided hypothesis 
testing with provision for early stopping in favor of the null hypothesis. J. Statistical Planning and 
Inference, 1994; 42:19-35. 
8.
Peto, R., Pike, M. C., Armitage, P., Breslow, N.E., Cox, D.R., Howard, S.V., Mantel, N., 
McPherson, K., Peto, J., Smith, P.G. Design and Analysis of Randomized Clinical Trials 
Requiring Prolonged Observation of Each Patient: I. Introduction and Design. Brit. J. 
Cancer 1976; 34:585–612.
9.
ICH Harmonised Tripartite Guideline. The Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. E 14. May 12, 2005. 
10. National Cancer Institute (NCI). Common Terminology Criteria For Adverse Events (CTCAE). 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html
11. Sprangers MAG, Groenvold M, Arraras JL, et. Al. The European Organization for Research and 
Treatment of Cancer Breast Cancer-Specific Quality-of-Life Questionnaire Module: First Results 
From a Three-Country Field Study. J Clin Oncol 1996; 14(10): 2756-2768.


Protocol A5481044  
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10. APPENDICES  
10.1.  Schedule of Activities 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures (Section 6)
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol. 
Visit Identifier
Screening
Active Treatment PhaseError! Reference source not 
found. (One Cycle = 28 days)
End of Treatment 
/ WithdrawalError! 
Reference source not found.
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-UpError! 
Reference source not found.
Cycles 1 and 2Error! 
Reference source not found.
Cycles t3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1Error! 
Reference source 
not found.
Day 15
Day 1Error! Reference 
source not found.
Time Window
r3d
r3d
r3d
r7d
r7d
r7d
Baseline Documentation
Informed Consent ProcessError! 
Reference source not found.
X
Medical / Oncological 
HistoryError! Reference source not found.
X
Baseline Signs / SymptomsError! 
Reference source not found.
X
Human Papillomavirus 
(HPV)-status analysisError! 
Reference source not found.
X
Physical Examination/Vital 
signsError! Reference source not found.
X
XError! Reference 
source not found.
X
X
Serum Pregnancy TestError! 
Reference source not found.
X
X
X
X
ECOG Performance Status
X
X
X
X
Laboratory Studies
HematologyError! Reference source not 
found.
X
XError! Reference 
source not found.
X
X
X
Blood ChemistryError! Reference 
source not found., Error! Reference source not 
found.
X
XError! Reference 
source not found.,
Error! Reference 
source not found.
X
X
X
X


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 40
Visit Identifier
Screening
Active Treatment PhaseError! Reference source not 
found. (One Cycle = 28 days)
End of Treatment 
/ WithdrawalError! 
Reference source not found.
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-UpError! 
Reference source not found.
Cycles 1 and 2Error! 
Reference source not found.
Cycles t3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1Error! 
Reference source 
not found.
Day 15
Day 1Error! Reference 
source not found.
Time Window
r3d
r3d
r3d
r7d
r7d
r7d
CoagulationError! Reference source not 
found.
X
XError! Reference 
source not found.
X
X
X
UrinalysisError! Reference source not 
found.
X
XError! Reference 
source not found.
X
X
X
12-Lead ECG (in triplicate)Error! 
Reference source not found.
X
XError! Reference 
source not found.
(C1 only)
X
X (C4, C7, C10)
X


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 41
Visit Identifier
Screening
Active Treatment PhaseError! Reference source not 
found. (One Cycle = 28 days)
End of Treatment 
/ WithdrawalError! 
Reference source not found.
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-UpError! 
Reference source not found.
Cycles 1 and 2Error! 
Reference source not found.
Cycles t3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1Error! 
Reference source 
not found.
Day 15
Day 1Error! Reference 
source not found.
Time Window
r3d
r3d
r3d
r7d
r7d
r7d
Special Laboratory Studies
Archival Tumor Tissue 
SpecimenError! Reference source not 
found.
X
De Novo Tumor 
SpecimensError! Reference source not 
found.
X
X
X
Blood Sample for Thymidine 
Kinase AssessmentsError! 
Reference source not found.
X(C1 only)
X(C1 only)
X(C3 only)
X
Disease Assessment 
Computed Tomography (CT)/ 
Magnetic Resonance Imaging 
(MRI) Scans of Head and Neck 
(oral cavity, oropharynx, 
hypopharynx, larynx), chest, 
abdomen (including the liver)
and any clinically indicated 
sites of disease; Clinical 
evaluation of superficial 
diseaseError! Reference source not found.
X
◄--►
Performed every 8 weeks (±7 days) from the 
date of randomization
X
X
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Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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Visit Identifier
Screening
Active Treatment PhaseError! Reference source not 
found. (One Cycle = 28 days)
End of Treatment 
/ WithdrawalError! 
Reference source not found.
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-UpError! 
Reference source not found.
Cycles 1 and 2Error! 
Reference source not found.
Cycles t3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1Error! 
Reference source 
not found.
Day 15
Day 1Error! Reference 
source not found.
Time Window
r3d
r3d
r3d
r7d
r7d
r7d
Other Clinical Assessments 
Drug ComplianceError! Reference 
source not found.
◄--►
Adverse Event (AE) 
ReportingError! Reference source not 
found.
X
X
X
X
X
X
X
X
Review Concomitant 
Medications/TreatmentsError! 
Reference source not found.
X
X
X
X
X
Quality of Life Questionnaire 
(EORTC-QLQ-C30 and 
EORTC-QLQ-H&N35) Error! 
Reference source not found.
X
X
X
X
Survival Follow-up
X


Protocol A5481044  
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Visit Identifier
Screening
Active Treatment PhaseError! Reference source not 
found. (One Cycle = 28 days)
End of Treatment 
/ WithdrawalError! 
Reference source not found.
4 weeks 
Post-Treatment
8 weeks 
Post-Treatment
Post-Treatment 
Follow-UpError! 
Reference source not found.
Cycles 1 and 2Error! 
Reference source not found.
Cycles t3
Study Day
Within 28 days 
prior to 
randomization 
unless specified 
otherwise
Day 1Error! 
Reference source 
not found.
Day 15
Day 1Error! Reference 
source not found.
Time Window
r3d
r3d
r3d
r7d
r7d
r7d
Study Treatment
Randomization 
X
Cetuximab (both treatment 
arms)
◄--►
Weekly IV Infusion
Palbociclib or Placebo
◄--►
Once daily with food on Day 1 to Day 21 of 
each cycle followed by 7 days off
Abbreviations: ◄--► = ongoing/continuous event; AE = adverse event; 
; CT = computed tomography; CRF = case report form; 
CxDy = Cycle x Day y; DNA = deoxyribonucleic acid; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; FFPE = formalin-fixed 
paraffin embedded; HPV = Human Papillomavirus; MRI = magnetic resonance imaging; SAE = Serious Adverse Event; WBC = white blood cells 
a.
Active Treatment Phase: All assessments should be performed prior to dosing with study medications on the visit day unless otherwise indicated.  
Acceptable time windows for performing each assessment are described in the column headers.  For the purposes of this trial, 1 cycle is 28 days in length. A
cycle could be longer than 28 days if persistent toxicity delays the initiation of the subsequent cycle. 
b.
Cycle 1/Day 1: Physical examination/vital signs, blood chemistry, hematology, urinalysis, coagulation, and 12-lead ECG are not required if acceptable 
screening assessment is performed within 7 days prior to randomization. 
c.
Cycle X, Day 1: In the event that the start of a new cycle is delayed due to treatment related toxicity, procedures required on Day 1 of the given cycle will be 
performed when palbociclib/placebo is resumed.  New cycle Day 1 procedures (ie, physical examination, ECOG performance status, ECG, Quality of Life 
questionnaires, blood chemistry, hematology, urinalysis, coagulation, and serum pregnancy test) that were performed prior to knowing the need to delay the 
start of the cycle do not need to be repeated (1) if not required to determine whether study drug may be resumed and (2) if performed within 7 days prior to 
study drug resumption. 
d.
End of Treatment/Withdrawal: End of Treatment/Withdrawal visit will be performed as soon as possible but no later than 4 weeks (ie, 28 days) r7 days 
from last dose of study treatment and prior to the initiation of any new anticancer therapy. 
e.
Post Treatment Follow-up:  After discontinuation of study treatment, post-treatment follow-up (including survival status and post-study anticancer therapy 
evaluation) will be collected every 2 months (r7 days) from the last dose of study treatment. Telephone contact is acceptable. 
f.
Informed Consent: Informed consent may be obtained greater than 28 days from randomization; however, it must be obtained prior to any protocol 
required assessments being performed. 
g.
Medical/Oncological History: To include information on prior anticancer treatments. 
h.
Baseline Signs/Symptoms: Baseline tumor related signs and symptoms will be recorded at the C1D1 visit prior to initiating treatment and then reported as 
AEs during the trial if they worsen in severity or increase in frequency. 
CCI


Protocol A5481044  
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i.
HPV-status: Patients must be HPV-negative to participate in this study.  Analytical method is per institutional standards. 
j.
Physical Examination/Vital signs: A full physical examination including an examination of all major body systems (including head, ears, eyes, nose, 
mouth, throat, neck, thyroid, lungs, heart, breasts, abdomen, and musculoskeletal), height (at screening only), weight, blood pressure and pulse rate, which 
may be performed by a physician, registered nurse or other qualified health care provider, will be required at Screening and C2D1. If screening assessment 
is not performed within 7 days prior to randomization, a full physical examination must be performed at C1D1.  Symptom-directed physical examinations, 
blood pressure and pulse rate assessments will be performed at subsequent visits. 
k.
Serum Pregnancy Test:  For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, and assayed in a 
certified laboratory, will be performed on 2 occassions prior to starting study therapy- once at the start of screening, and once at the baseline visit, 
immediately before investigational product administration.  A negative pregnancy result is required before the patient may receive the investigational 
product.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected), repeated at Day 1 of each cycle, and at the end of the study to confirm the patient has not become pregnant during the study.  
Pregnancy tests may also be repeated as per request of institutional review boards (IRBs)/ethics committees (ECs) or if required by local regulations. In case 
of a positive confirmed pregnancy, the patient will be withdrawn from study medication and from the study. Two methods of highly effective contraception 
must be used throughout the study and continue for 6 months after the last dose of cetuximab.  See Section Error! Reference source not found. for further 
information. 
l.
Hematology, and Blood Chemistry Panel, and Urinalysis: Hematology includes hemoglobin, WBC, absolute neutrophils, absolute lymphocytes, and 
platelet count. Blood chemistry includes AST/ALT, alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, BUN (or 
urea), serum creatinine, uric acid, phosphorous (or phosphate), albumin, fasted glucose, and hemoglobin A1c.  Additional hematology/chemistries panels 
may be performed as clinically indicated. Fasting glucose will be acquired at baseline C1D1, C1D15, and C2D1.  For all patients, 8 weeks after the 
completion of therapy, blood chemistry panel consisting of magnesium, total calcium, and potassium must be checked. If abnormalities are observed, an 
ECG can be performed at the discretion of the investigator to check QTc.  Urinalysis will be conducted via urine dipstick for urine protein: if the result is 
positive, further diagnostic testing will be performed as clinically indicated. 
m. Hemoglobin A1c: Hemoglobin A1c will be measured at C1D1, during the active treatment phase every 3 months from the date of randomization (ie, C4D1, 
C7D1, C10D1, etc.), and at the End of Treatment visit.  
n.
Coagulation: Coagulation analysis includes PT or INR and PTT. 
o.
12-Lead ECG: All ECGs should be obtained after a fast of at lease 1 hour.  For the purpose of this study, triplicate ECGs are defined as three consecutive 
ECGs performed approximately 2 minutes apart but within 10 minutes for all 3 ECGs at the protocol-specified timpoints to determine the mean QTc 
interval. 
  
C
C
I


Protocol A5481044  
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r.
Archival Tumor Tissue Specimen: All patients will provide a FFPE archival tumor specimen, specifically a FFPE tissue block that contain sufficient tissue 
to generate at least 15 unstained slides, each with tissue sections that are 5 microns thick, or at least 15 unbaked glass slides, each containing an unstained 
5 micron FFPE tissue section if FFPE tissue block cannot be submitted.  If an archival tumor tissue sample is not available, a de novo tumor biopsy 
specimen must be obtained.  Specimens will be sent to the Sponsor-designated central laboratory.  Details for the handling of these specimens, including 
processing, storage, and shipment will be provided in the Study Manual.  
s.
De Novo Tumor Specimens: Optional de novo tumor biopsy collection at screening, C1D15 or C2D15 (pre-dose, one time point only) and at the time of 
progression/End of Treatment is strongly encouraged; no more than 3 timepoints should be collected in total. In all cases, these specimens will be provided 
in addition to the archival tumor tissue specimen that is required for enrollment.  Details for handling of these specimens including processing, storage, and 
shipment will be provided in the Study Manual.  
t.
Blood Sample for Thymidine Kinase Assessments: 6 ml blood specimen optimized for serum preparation for TK activity assessment will be collected at 
C1D1 (pre dose), C1D15 (pre-dose), C3D1 (pre-dose) and at End of Treatment.  Details for handling of these specimens including processing, storage, and 
shipment will be provided in the Study Manual. 
u.
Blood Sample for CNA Profiling: 10 ml blood specimen optimized for plasma preparation for nucleic acid analysis will be collected at C1D1 (pre dose), 
C3D1 (pre-dose) and at End of Treatment.  Details for handling of these specimens including processing, storage, and shipment will be provided in the Study 
Manual. 
v.
Disease Assessments: Please refer to the  
 


Protocol A5481044  
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w.
Tumor Assessment Requirements for details and timing of procedures. 
x.
Drug Compliance: Palbociclib and placebo bottle(s), including any unused capsules, will be returned to the clinic for drug accountability.  Drug 
accountability will be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle. 
y.
AEs: For SAEs, the active reporting period begins from the time that the patient provides informed consent through and including 28 calendar days after the 
last administration of the investigational product.  Following the active safety reporting period, other SAEs of which the investigator becomes aware should 
be reported to Pfizer, unless the SAE is attributed by the investigator to complications of either the underlying malignancy or any subsequent anti-cancer 
therapy or to the patient’s participation in a subsequent clinical study.  AEs (serious and non-serious) should be recorded on the CRF from the time the 
patient has taken at least one dose of study treatment through last patient visit. 
z.
Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to 28 days after the last dose of study treatment.  If a patient begins new therapy before the 28-day time period is complete, concomitant medication 
information will not be recorded (from the start date of the new therapy). This includes H1 antagonists pre-medication to alleviate cetuximab infusion 
reactions.  
aa. EORTC-QLQ-C30 and EORTC-QLQ-H&N35 Assessments: Patients will complete questionnaires prior to any study or medical procedure on Day 1 of 
Cycles 1, 2 and 3 and then Day 1 of every other cycle thereafter starting with Cycle 5 (ie, Cycle 5, 7, 9, etc.), and at the End of Treatment visit.  Four weeks 
after discontinuation of study treatment due to progressive disease, patients will be completing the questionnaires at the Follow-up Visit.  All self-assessment 
questionnaires must be completed by the patients while in the clinic and cannot be taken home.  Interviewer administration in clinic may be used under 
special circumstances, but family members are not permitted to assist with questionnaire administration. 
 
 


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10.2. Tumor Assessment Requirements Flowchart 
Screeninga
Treatment Periodb
End of Treatment Visitc
CT or MRI of Head and Neck (oral cavity, 
oropharynx, hypopharynx, larynx)d
Requirede
Required
Required
CT or MRI of Chest and Abdomen 
(including the liver)d
Requirede
Required
Required
CT or MRI of any other site of disease, as 
clinically indicated.
Requirede, f
Required for sites of disease 
identified at screening.
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere.
Photographs of all superficial lesions as 
applicableg
Required
Required for sites of disease 
identified at screening.
Required for sites of disease identified at screening, unless 
disease progression has been confirmed elsewhere.
a.
Screening scans must occur within 4 weeks (ie, 28 days) prior to randomization unless otherwise specified. 
b.
Tumor assessment must be done during the treatment period, every 8 weeks (r7 days) until radiographically and/or clinically (ie, for photographed or 
palpable lesions) documented PD as per RECIST v.1.1, initiation of new anticancer therapy, or discontinuation of patient from overall study participation 
(eg, death, patient's request, lost to follow up), whichever occurs first.  The schedule of assessments should be fixed according to the calendar, regardless 
of treatment delays/interruptions.  Imaging assessments are to be scheduled using the randomization date as the reference date for all time-points and are 
NOT to be scheduled based on the date of the previous imaging time-point.  Imaging assessment delay to conform to treatment delay is not permitted.  The 
same tumor assessment technique MUST be used throughout the study for a given lesion/patient. 
c.
Patients who have already demonstrated objective disease progression as per RECIST v.1.1 do not need to have scans repeated at the end of treatment visit 
or during the post-treatment follow-up.  For patients who do not have documented objective disease progression at time of study treatment discontinuation, 
tumor assessment will continue to be performed every 8 weeks (r7 days) until radiographically and/or clinically confirmed objective disease progression, 
initiation of new anticancer therapy, or discontinuation of patient from overall study participation (eg, death, patient's request, lost to follow-up). 
d.
The CT scans, including brain CT scan if applicable, should be performed with contrast agents unless contraindicated for medical reasons.  If IV contrast is 
medically contraindicated, the imaging modality to be used to follow the disease (either CT without contrast or MRI) should be the modality which best 
evaluates the disease, and the choice should be determined by the investigator in conjunction with the local radiologist.  MRI of the abdomen can be 
substituted for CT if MRI adequately depicts the disease.  However, MRI of the chest should not be substituted for CT of chest even if IV contrast is 
contraindicated.  In such case CT will be performed without contrast.  If MRI is used to follow-up bone lesion(s) it must be performed a few days before 
any treatment that may affect bone-marrow cellularity (eg, G-CSF).
e.
Radiographic assessments obtained per the patient’s standard of care prior to randomization into the study do not need to be repeated and are acceptable to 
use as baseline evaluations, if (1) obtained within 28 days before randomization, (2) they were performed using the method requirements outlined in 
RECIST v.1.1 (3) the same technique/modality can be used to follow identified lesions throughout the trial for a given patient, and (4) appropriate 
documentation indicating that these radiographic tumor assessments were performed as standard of care is available in the patient’s source notes. 
f.
Baseline brain scans are required in patients with a history of metastatic brain disease.  Brain scans performed before the signing of informed consent as 
routine procedures (but within 6 weeks before randomization) do not need to be repeated and may be used as baseline assessments as long as (1) tests were 
performed using the method requirements outlined in RECIST v.1.1 (2) the same technique/modality can be used to follow identified lesions throughout 
the trial for a given patient (3) appropriate documentation indicating that these radiographic tumor assessments were performed as standard of care is 
available in the patient’s source notes.  Post-baseline repeat brain scans will be required only if new metastases are suspected.


Protocol A5481044  
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g.
Clinical assessment of superficial disease must be carried out on the same date as the imaging studies and will include photographs of all superficial 
metastatic lesions.  All lesion measurements must be recorded in the CRF.
Notes: 
- Radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression at the discretion of the investigator.  If progressive disease is 
confirmed per RECIST v.1.1, patients are expected to discontinue study therapy and begin the follow-up phase of the trial.


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10.3. RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247  
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions   
Lesions that can be accurately measured in at least one dimension. 
x
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater  
when assessed by CT or MRI  (slice thickness 5-8 mm) 
x
Lesions with longest diameter at  least 20 mm when assessed by Chest X-ray   
x
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper   
x
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE:  The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions.  
Non-measurable disease  
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical examination that are not measurable 
by reproducible imaging techniques. 
x
Bone disease:  Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline.   
x
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
Normal sites 
x
Cystic lesions: Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease.  Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above. If 
non-cystic lesions are also present, these are preferred as target lesions. 
x
Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
RECORDING TUMOR ASSESSMENTS  
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start. For an adequate baseline assessment, all required scans 


Protocol A5481044  
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must be done within 28 days prior to treatment and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.   
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. Target 
lesions should be selected on the basis of size (longest lesions) and suitability for accurate 
repeated measurements.  Record the longest diameter for each lesion, except in the case of 
pathological lymph nodes for which the short axis should be recorded.  The sum of the 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at 
baseline will be the basis for comparison to assessments performed on study.  
x
 If two target lesions coalesce the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used. 
x
Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded.. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
Non-target disease  
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE STATUS AT EACH EVALUATION. 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.   
Target disease 
x
Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis < 
10 mm).  All target lesions must be assessed. 
x
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  All 
target lesions must be assessed.   
x
Stable: Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  


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Stable can follow PR only in the rare case that the sum increases by less than 20% from 
the nadir, but enough that a previously documented 30% decrease no longer holds.   
x
Objective Progression (PD):  20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm.   
x
Indeterminate. Progression has not been documented, and  
x
one or more target measurable lesions have not been assessed  
x
or assessment methods used were inconsistent with those used at baseline 
x
or one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure) 
x
or one or more target lesions were excised or irradiated and have not reappeared or 
increased.   
Non-target disease 
x
CR: Disappearance of all non-target lesions and normalization of tumor marker levels. 
All lymph nodes must be ‘normal’ in size (<10 mm short axis).
x
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the normal limits.  
x
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD or 
PR in target disease, progression due to unequivocal increase in non-target disease should 
be rare.   
x
Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at baseline. 
New Lesions  
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion. 
Supplemental Investigations 
x
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR. 
x
If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status.  
Subjective progression 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 


Protocol A5481044  
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indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment. 
 
BOR Based on Unconfirmed Objective Status 
Unconfirmed CR (uCR):  One objective status of CR documented before progression or 
start of new anti-cancer therapy.  
Unconfirmed PR (uPR):  One objective status of PR documented before progression and 
start of new anti-cancer therapy, but not qualifying as uCR. 
Table 1. Objective Status at each Evaluation 
Target Lesions
Non-target Disease
New
Lesions
Objective 
status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
SD
Indeterminate or Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:Table 2. Objective Status at each Evaluation for Patients with Non-Target 
Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes*
PD
* New lesions must be unequivocal


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SD:  At least one objective status of SD or better documented at least X (>=12) weeks after 
start date and before progression and the start of new anti-cancer therapy but not qualifying 
as uCR or uPR.
PD: Progression documented within Z (<=12) weeks after start date and not qualifying as 
uCR, uPR or SD. 
NE: All other cases.  Note that reasons for NE should be summarized and the following 
reasons could be used:  
x
Early death (Note: death prior to X (<12) weeks after start date)
x
No post-baseline assessments  
x
All post-baseline assessments have overall response NE 
x
New anti-cancer therapy started before first post-baseline assessment 
x
SD too early (<X (12)) weeks after start date) 
x
PD too late (>Z (12) weeks after start date) 
Special and rare cases where BOR is NE due to both early SD and late PD will be 
classified as ‘SD too early’.
An objective status of PR or stable cannot follow one of CR.  Stable can follow PR only in 
the rare case that tumor increases by less than 20% from the nadir, but enough that a 
previously documented 30% decrease from baseline no longer holds.   


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10.4. Rules for Determining PFS Status and Date 
Situation
Date of Progression/Censoring1
Outcome
Inadequate baseline 
assessment 
Randomization date (Day 1)
Censored
No on-study assessments
Randomization date (Day 1)
Censored
Alive and no Progression 
Date of last objective tumor assessment 
documenting no progression
Censored
Progression Documented on 
or between scheduled tumor 
assessments
Date of first objective tumor assessment 
documenting objective progression
Progressed 
(Event)
Patients are removed from 
the study (withdrew the 
consent, lost to follow up, etc.)  
prior to progression or death
Date of last objective tumor assessment 
documenting no progression
Censored
New anticancer treatment 
prior to progression or death
Date of last objective tumor assessment 
documenting no progression prior to 
new anticancer treatment
Censored
Death prior to first planned 
tumor assessment 
Date of death
Death (Event)         
Death without objective 
progression prior to 
treatment discontinuation2
Date of death
Death (Event)
Death or progression after 2 
or more missed tumor 
assessments
Date of last objective tumor assessment 
documenting no progression prior to the 
event
Censored
1 For date of censorship, if a tumor assessment takes place over a number of days (e.g., superficial lesions one 
day, scans another), the last date is used as the assessment date. 
 


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10.5. Data Derivation Details 
Enrollment/Randomization 
Date of assignment of the randomization number
Study Day 1
Randomization day
Study Day (At/Post randomization 
date) 
Assessment Date – randomization Date +1
Study Day (Prior randomization date)
Assessment Date – randomization date
Treatment Day 1
1st Dose date
Treatment Day (At/Post 1st dose date) 
Assessment Date – 1st Dose Date +1
Treatment Day (Prior 1st dose date)
Assessment Date – 1st dose date
Treatment start
Day 1 of Cycle 1
Day 1 (cycle start date) of Cycle x
Day 1 of a cycle is every 28 days unless there is a 
dosing delay.
Cycle length (all but final cycle)
Cycle length is 28 days (previous cycle length may 
exceed planned length if there is a delay in study 
treatment administration).
Final cycle
For patients off treatment, from Day 1 of final cycle 
to 28 days after final dose or until start of new 
anticancer treatment (whichever comes first).  
For patients on treatment, from Day 1 of most recent 
cycle start to protocol specified cycle length.
Follow-up Period for AEs
From 28 days after final dose until start of new 
anticancer treatment (whichever comes first).  
Baseline lab values
From date closest to, but prior to, start of study 
treatment. 
Baseline triplicate ECGs
Cycle 1 Day 1 dose or from date closest to, but prior 
to, start of study treatment if C1D1 is not available. 
Tumor assessment baseline values
From date closest but prior to  first dose.  
Adequate baseline tumor assessment
Within 35 (28 + 7) days prior to first dose.
Maximum diameter reported for each target lesion 
listed.  All required pre-treatment scans done.
Cycle k treatment delayed.
If study treatment administration is delayed for cycle 
k then cycle k-1 is extended. 


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10.6. Study Treatment Modification and Compliance  
10.6.1. Dose Modification 
In the event of significant treatment-related toxicity, palbociclib/placebo and/or cetuximab 
dosing may be interrupted or delayed and/or reduced as described below.  In the event of 
multiple toxicities, dose modification should be based on the worst toxicity observed.  
Patients are to be instructed to notify Investigators at the first occurrence of any adverse sign 
or symptom. 
Dose modifications may occur in three ways: 
x
Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 
x
Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start; 
x
In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
10.6.2. Summarizing Relative Dose Intensity (RDI)  
The following types of summaries are proposed for administration of palbociclib and 
cetuximab.
When palbociclib is administered orally once a day for 21 days of every 28-day cycle 
followed by 7 days off treatment (cyclical dosing) in combination with cetuximab (IV), the 
following summaries can be presented: 
x
RDI for palbociclib: by Cycle and Overall  
x
RDI for cetuximab: by Cycle and Overall 
Note: the denominator for tables summarizing “cetuximab” will be all patients who received 
at least one dose of cetuximab and for tables summarizing “palbociclib” will be all patients 
who took at least one dose of palbociclib. 
Examples for the summaries described in above are included in the tables below. 
Conventions: 
x
The Intended Dose Intensity is the same for all cycles: the daily dose is fixed at the 
start of treatment rather than start of a cycle and the intended treatment duration is the 
same for the entire dosing period, including last cycle (e.g. for a 3/1 dosing schedule, 
all cycles have an intended duration of 4 weeks);  
x
Actual Dose Intensity is calculated based on actual cycle length in all but last cycle 
where it is fixed at the intended length (e.g. 4 weeks for a 3/1 dosing schedule) 


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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Table 1 
Treatment/
Summary Type
Calculation of Relative Dose Intensity (RDI)
Palbociclib or 
Placebo 
/ By Cycle
100
*
ilyDose
IntendedDa
sity
yDoseInten
ActualDail
RDI  
%Where:
Intended Daily Dose (mg/day in 21/7 schedule) = 125 
Actual Daily Dose Intensity (mg/day in 21/7 schedule) = 
Actual Average Daily Dose (mg/day in x/y schedule) *
(Actual Dose Days / Intended Dose Days ) *
(Intended Cycle Duration / Actual Cycle Duration)
x
Actual Average Daily Dose (mg/day in x/y schedule) = 
Actual Total Dose / Actual Dose Days  
x
Intended Dose Days =
For  non-last cycle: 21
For last cycle: minimum (21, Actual Cycle Duration)
x
Intended Cycle Duration =
For non-last cycle: 28
For last cycle: minimum (28, Actual Cycle Duration)
Palbociclib or 
Placebo
/ Overall
100
*
ilyDose
IntendedDa
sity
yDoseInten
ActualDail
RDI  
%
Where:
Intended Daily Dose (mg/day in 21/7 schedule) = 125 
Actual Daily Dose Intensity (mg/day in 21/7 schedule) = 
Actual Average Daily Dose (mg/day in x/y schedule) *
(Actual Dose Days / Intended Dose Days ) *
(Intended Cycle Duration / Actual Cycle Duration)
x
Actual Average Daily Dose (mg/day in x/y schedule) = 
Sum over all cycles of “Actual Total Dose” /
Sum over all cycles of “Actual Dose Days”
x
Intended Dose Days = Sum over all cycles of “Intended Dose Days”  
x
Intended Cycle Duration = Sum over all cycles of “Intended Cycle 
Duration”


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 58
Treatment/
Summary 
Type
Calculation of Relative Dose Intensity (RDI)
Cetuximab 
/ By Cycle
Possible 
dose 
reductions 
or potential 
overdose, 
and
dose 
interruption
s
100
*
erageDose
IntendedAv
ensity
ageDoseInt
ActualAver
RDI  
%
Where:
Intended Average Dose ((mg/sqm)/Q7d) =ቄ
ͶͲͲͳͳ
ʹͷͲǡͳͳ
ActualAverageDoseIntensity = 
Actual Average Dose ((mg/sqm)/Qxd) in the Cycle
*Factor in dose interruptions:
x
Factor in dose reductions or potential overdose:
Actual Average Dose ((mg/sqm)/Qxd) in the Cycle = 
Actual Total Dose in the Cycle / Actual Freq of Qxd in the Cycle  
x
Factor in dose interruptions:
For Last Cycle:
Actual Freq of Qxd in the Cycle / CEIL (Actual Cycle Duration in the Cycle/
7)
ForC1W1:
1 / (Actual Cycle Duration of C1W1 in the Cycle/ 7)     
For Cycle 1 (exclude C1W1):
‘Actual Freq of Qxd in the Cycle 1 – 1 (exclude C1W1) / (Actual Cycle 
Duration - actual duration of C1W1) in the Cycle/ 7)
For other Cycles: 
Actual Freq of Qxd in the Cycle / (Actual Cycle Duration in the Cycle/ 7)


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
Page 59
Cetuximab 
/ Overall
Possible 
dose 
reductions
or potential 
overdose,
and
dose 
interruption
s
Footnote: 
Overall 
column for 
‘Overall 
Actual 
Average 
Dose, 
Overall 
Intended 
Average 
Dose, 
Overall 
Actual Dose 
Intensity, 
and RDI  
are 
excluding 
C1W1
100
*
erageDose
IntendedAv
ensity
ageDoseInt
ActualAver
RDI  
%
Overall Intended Average Dose ((mg/sqm)/Q7d) = 
400 – for C1W1
250 – for all other cycle’s overall 
Overall Actual Dose Intensity ((mg/sqm)/Q7d) = 
Overall Actual Average Dose (mg/Qxd) * [Overall Actual Freq of Qxd -1 ] /
[CEIL(Overall Actual Cycle Duration / 7) - 1]  }
x
Factor in dose reductions or potential overdose:
Overall Actual Average Dose ((mg/sqm)/Qxd) (exclude C1W1) =
[ Overall Actual Total Dose - Actual dose of C1W1 (Note: Exclude C1W1) ] /
[Overall Actual Freq of Qxd - 1(Note: Exclude C1W1) ]
x
Factor in dose interruptions:
[Overall Actual Freq of Qxd - 1 (Note: Exclude C1W1)] /
[CEIL(Overall Actual Cycle Duration ) / 7)  – 1]
x
O. Actual Freq of Qxd = Sum over all cycles of “Actual Freq of Qxd”
x
O. Actual Cycle Duration = Sum over all cycles of “Actual Cycle Duration”
Cetuximab 
(Q7d)
/ Overall –
RDI 
(Include 
C1W1)   
100
*
250
*
]1
)
7
/
(
[
400


 
n
talDuratio
ualCycleTo
OverallAct
CEIL
se
ualTotalDo
OverallAct
RDI
%


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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10.7. European Organisation for Research and Treatment of Cancer Quality of Life 
Instrument (EORTC-QLQ-C30) 


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Statistical Analysis Plan Amendment V3, 26Apr2018 
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10.8. European Organisation for Research and Treatment of Cancer Head and Neck 
Module 35 (EORTC-QLQ-H&N35) 


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Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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10.9. List of Abbreviation 
Abbreviation
Term
AE
Adverse Event
ALT
Alanine Aminotransfersae
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransfersae
AUC
Area Under the Curve
bid
Bis in Die (twice a day)
CAG
Clinical Assay Group
CCND1
Cyclin D1
CDK
Cyclin-Dependent Kinase
CDKN2A, p16Ink4A
Cyclin-Dependent Kinase Inhibitor 2A
cf
Circulating-Free
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
CMH
Cochran-Mantel-Haenszel
CNS
Central Nervous System
CR
Complete Response
CRF
Case Report Form
CSA
Clinical Study Agreement
CT
Computed Tomography
CTA
Clinical Trial Application
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CxDy
Cycle x, Day y (refer to Section 10.1. Schedule of Activities)
CYP
Cytochrome P-450
d
Day
DDI
Drug-Drug Interaction
dL
Deciliter
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
DU
Dispensable Unit
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
E-DMC
External Data Monitoring Committee
EDP
Exposure During Pregnancy
EDTA
Ethylenediaminetetraacetic acid
EGFR
Epidermal Growth Factor Receptor
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire
CCI


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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EORTC-QLQ-
H&N35
European Organisation for Research and Treatment of Cancer Head 
and Neck Module 35
ER
Estrogen Receptor
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration 
FDAAA
Food and Drug Administration Amendments Act
FFPE
Formalin-Fixed Paraffin Embedded
FSH
Follicle-Stimulating Hormone
g
gram
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
H1
Histamine Antagonist of the H1 Receptor
Hb
Hemoglobin
HDPE
High Density Polyethylene
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
HPV
Human Papillomavirus
HR
Hormone Receptor or Hazard Ratio (depending on context)
HRQL
Health-Related Quality of Life
HSR
Hypersensitivity Reaction
IB
Investigator’s Brochure
IC50
Concentration of 50% Inhibition 
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ID
Identification
IHC
Immunohistochemistry
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Randomization Technology or Interactive Response 
Technology (depending on context)
IUD
Intrauterine Device
IV
Intravenous
IVR
Interactive Voice Response
IWR
Interactive Web Response
L
Liter
LFT
Liver Function Test
LPLV
Last Patient Last Visit
m2
Square meter, also sqm
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MID
Minimally Important Difference
mIU
Milli-International Unit


Protocol A5481044  
Statistical Analysis Plan Amendment V3, 26Apr2018 
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mL
milliliter
mm3
Cubic millimeter
MRI
Magnetic Resonance Imaging
msec
millisecond
MTD
Maximum Tolerated Dose
N/A
Not Applicable
NABSA
Nucleic Acid Sequence Based Amplification
NCI
National Cancer Institute
NGS
Next-Generation Sequencing
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
PCD
Primary Completion Date
PCR
Polymerase Chain Reaction
PD
Progressive Disease, Progression of Disease, or Pharmacodynamic 
(depending on context)
PFS
Progression-Free Survival
PK
Pharmacokinetic
PPI
Proton-Pump Inhibitor
PR
Partial Response or PR interval is measured from the beginning of 
the P wave to the beginning of the QRS complex (depending on 
context)
PRO
Patient-Reported Outcome
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QD
Quaque Die (once daily)
QOL
Quality of Life
QRS
The QRS complex is a name for the combination of three of the 
graphical deflections seen on a typical electrocardiogram.
The QRS complex reflects the rapid depolarization of the right and 
left ventricles
QT
Time between the start of the Q wave and the end of the T wave in 
the heart's electrical cycle
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett's fomula
QTcF
QT interval corrected for heart rate using Fridericia's fomula
RB/Rb
Retinoblastoma
RECIST
Response Evaluation Criteria in Solid Tumors
R/M
Recurrent/Metastatic
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
RR
The interval between an R wave and the next R wave
SAE
Serious Adverse Event


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Statistical Analysis Plan Amendment V3, 26Apr2018 
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SAP
Statistical Analysis Plan
SCCHN
Squamous Cell Carcinoma of the Head and Neck
SCL
Supply Chain Lead
SD
Stable Disease or Standard Deviation (depending on context)
SOA
Schedule of Activities
SOC
System Organ Class
SPC
Summary of Product Characteristics
sqm
Square meter, also m2
SRSD
Single Reference Safety Document
t½
Terminal Elimination Half-life
TdP
Torsade de Pointes
Tmax
Time for Cmax
ULN
Upper Limit of Normal
US
United States
v
version
WBC
White Blood Cells
CC
CCI