Conditions: Head and Neck Neoplasms
Keywords: Squamous cell cancer of the head and neck Squamous cell carcinoma Head and neck cancer Neoplasms by site
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 87
Healthy volunteers: no

Brief summary:
This study will test an investigational study drug called patritumab. It is a 'randomized study' which means participants have an equal chance of being assigned to receive the experimental medication (patritumab) or a substance that looks like the experimental product, but is not (placebo). Patritumab may work when combined with other medications that are approved for the treatment of head and neck cancer. They are called cetuximab, cisplatin or carboplatin. All participants will receive the other medications approved for treatment of head and neck cancer, even if they do not receive the experimental product.

Detailed description:
Main objective of the trial:

The main objective of the trial is to evaluate progression-free survival (PFS) in the heregulin (HRG) high expression population from subjects treated with patritumab + cetuximab + platinum-based therapy compared to placebo + cetuximab + platinum-based therapy.

Arms:
arm 1: All participants receive patritumab with cetuximab plus platinum-based therapy (cisplatin or carboplatin) arm 2: All participants receive placebo with cetuximab plus platinum-based therapy (cisplatin or carboplatin)

Interventions: intervention 1: Patritumab intervention 2: Cetuximab intervention 3: Cisplatin intervention 4: Carboplatin intervention 5: Placebo
Intervention descriptions: intervention 1: Patritumab initial loading dose is 18 mg/kg IV over 60 minutes followed by a maintenance dose of 9 mg/kg IV over 60 minutes (± 10 minutes) every three weeks intervention 2: Cetuximab 400 mg/mg/m\^2 IV loading dose, followed by 250 mg/m\^2 weekly intervention 3: Cisplatin at 100 mg/m\^2 IV infused over 1 hour, every three weeks up to a maximum of 6 cycles intervention 4: Carboplatin IV over 30 to 60 minutes, every 3 weeks for a maximum of 6 cycles intervention 5: Placebo to match patritumab

Protocol document:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL
RANDOMIZED, PLACEBO-CONTROLLED, 
DOUBLE-BLIND PHASE 2 STUDY OF 
PATRITUMAB (U3-1287) IN COMBINATION WITH 
CETUXIMAB PLUS PLATINUM-BASED THERAPY 
IN FIRST LINE SETTING IN SUBJECTS WITH 
RECURRENT OR METASTATIC SQUAMOUS 
CELL CARCINOMA OF THE HEAD AND NECK
PROTOCOL U31287-A-U203
IND NUMBER 102,396
EUDRACT: 2015-002222-40
GLOBAL – VERSION 4.0, 14 JUN 2016
VERSION 3.0, 29 JAN 2016
VERSION 2.0, 27 AUG 2015
VERSION 1.0, 25 JUN 2015
SPONSOR
Daiichi Sankyo, Inc.
399 Thornall Street 
Edison, NJ 08837, United States
CONFIDENTIALITY STATEMENT
Information contained in this document is proprietary to Daiichi Sankyo.  The 
information is provided to you in confidence which is requested under an agreed upon 
and signed Confidentiality and Disclosure Agreement.  Do not give this document or any 
copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative of Daiichi Sankyo.


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PROTOCOL SYNOPSIS
IND Number:
102,396
Protocol Number:
U31287-A-U203
Investigational Product:
Patritumab (U3-1287)
Active Ingredient(s)/INN:
Fully human monoclonal immunoglobulin G Subclass 1 
(IgG1) antibody directed against human epidermal growth 
factor receptor 3 (HER3) 
Study Title:
Randomized, Placebo-Controlled, Double-Blind Phase 2 Study 
of Patritumab (U3-1287) in Combination with Cetuximab plus 
Platinum-Based Therapy in First Line Setting in Subjects with 
Recurrent or Metastatic Squamous Cell Carcinoma of the Head 
and Neck
Study Phase:
Phase 2 
Indication Under Investigation:
Recurrent or metastatic squamous cell carcinoma of the head 
and neck (SCCHN)
Study Objectives:
Primary Objective

To evaluate progression-free survival (PFS) in the 
heregulin (HRG) high expression population from subjects 
treated with patritumab + cetuximab + platinum-based 
therapy compared to placebo + cetuximab + platinum-
based therapy.
Secondary Objectives

Evaluate overall survival (OS)

Evaluate overall response rate (ORR) 

Refine the cutoff between heregulin  high and low 
expression based on clinical data from this study

Assess the population PK of patritumab in subjects with 
SCCHN

Assess the PK parameters of serum cetuximab and 
platinum concentrations when cetuximab and cisplatin or 
carboplatin (platinum-based therapy) are coadministered 
with patritumab in a sub group (n = 30) of subjects

Evaluate the incidence of human antihuman antibody 
(HAHA) formation (anti-patritumab antibodies)

Evaluate the safety and tolerability of the combination of 


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patritumab + cetuximab + platinum-based therapy in first-
line treatment of subjects with SCCHN
Exploratory Objectives

Duration of response, time to response, time to disease 
progression, duration of stable disease from subjects 
treated with patritumab + cetuximab + platinum-based 
therapy compared to those treated with placebo + 
cetuximab + platinum-based therapy 

Explore potential exposure-response and possibly other 
biomarker relationships

Evaluate disease-specific patient reported outcomes  using 
the Functional Assessment of Cancer Therapy-Head and 
Neck questionnaire, the 10-item FACT – Head and Neck 
Symptom Index, and the EuroQoL 5 Dimensions-5 Levels.
Study Design:
This is a multicenter, randomized, placebo-controlled, double 
blind Phase 2 study to evaluate the PFS and safety in 
recurrent/metastatic first-line SCCHN in subjects treated with 
patritumab plus cetuximab plus platinum-based therapy 
compared with subjects randomized to the control arm 
consisting of placebo plus cetuximab plus platinum-based 
therapy.
Study Duration:
For the purpose of collecting survival data, the duration of the 
study will be until all subjects have died or a minimum of 13 
months after the last subject is randomized whichever comes 
first, approximately 22 months for PFS and 25 months for OS.
Subjects receiving clinical benefit from treatment will be 
offered the opportunity to continue therapy with patritumab 
and cetuximab (platinum-based therapy administered for no 
more than 6 cycles) in the extension phase of this protocol.
Study Sites and Location:
Approximately 35 sites in Europe.
Planned Sample Size:
Approximately 105 subjects will be randomized to the 
patritumab and the control arms in a 2:1 stratified fashion 
(approximately 70 HRG-high and approximately 35 HRG-low 
subjects).  When one arm is filled with the required sample 
size, the enrollment in that arm will cease and the other arm 
will be filled. 
Subject Eligibility Criteria:
Key Inclusion Criteria
1.
Adult subjects ≥18 years old


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2.
Histologically confirmed recurrent disease or 
metastatic SCCHN tumor and/or from its lymph nodal 
metastases originating from the oral cavity, 
oropharynx, hypopharynx, and larynx
3.
Heregulin expression level is required

Samples must be taken from subjects who
have recurrent or metastatic disease. These 
samples can be from either rec/met archived or 
fresh biopsy samples

No cancer treatment between time of biopsy 
and submission of sample

Surgical or core needle biopsy is acceptable

Fine-needle aspiration or cytology is not 
acceptable for biopsies
4.
Human papilloma virus (HPV) status or p16 (surrogate 
for HPV) is required. These results must come from 
tumor tissue. These results may be obtained from 
either a local lab or samples sent to the central lab

HPV or p16 status can be from any tumor 
biopsy material from initial diagnosis
5.
Measurable disease per Response Evaluation Criteria 
in Solid Tumor (RECIST) Version 1.1
6.
Eastern Cooperative Oncology Group performance 
status 0 or 1
7.
Hematological function, as follows:

Absolute neutrophil count  ≥ 1.5 x 109/L 

Platelet count ≥ 100 x 109/L

Hemoglobin ≥ 10 g/dL
8.
Renal function, as follows:

Estimated serum creatinine clearance
(mL/min) or glomerular filtration rate (GFR)
≥60 mL/min for cisplatin and ≥30 mL/min
for carboplatin
9.
Hepatic function, as follows: 

Aspartate aminotransferase  ≤ 2.5 x upper 
limit of normal (ULN) (if liver metastases are 
present, < 5 x ULN)

Alanine aminotransferase  ≤ 2.5 x ULN (if 


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liver metastases are present, < 5 x ULN)

Alkaline phosphatase ≤ 2.0 x ULN (if bone or 
liver metastases are present, < 5 x ULN)

Bilirubin ≤ 1.5 x ULN
10. Prothrombin time  or partial thromboplastin time ≤ 
1.5 x ULN
11. Women of childbearing potential must have a negative 
serum pregnancy test performed within 14 days prior 
to enrollment (where demanded by local regulations, 
test may be required within 72 hours prior to 
enrollment)
12. Adult subjects of child-bearing potential must agree to 
use double-barrier contraceptive measures. Two of the 
following precautions must be used: bilateral 
vasectomy, bilateral tubal ligation, intrauterine 
device (IUD), combined (estrogen and progesterone 
containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, 
transdermal), progesterone-only hormonal 
contraception associated with inhibition of ovulation 
(oral, injectable, implantable), intrauterine hormone-
releasing system (IUS), condom with spermicide, 
abstinence. These contraception measures must be 
used for the entire duration of the study and for 6 
months after the last study dose is received
13. Subjects must be willing and able to comply with 
schedule visits, treatment plan, laboratory tests, and 
other study procedures
14. Provided written informed consent(s)
Key Exclusion Criteria
1.
Left ventricular ejection fraction  <50%
2.
Prior epidermal growth factor receptor  targeted 
regimen
3.
No HRG expression result
4.
No HPV or p16 status
5.
Prior anti-HER3 therapy
6.
Prior chemotherapy for recurrent/metastatic disease
7.
Anti-cancer therapy between biopsy and submission of 
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8.
Presence of squamous cell tumors of the nasopharynx
9.
History of other malignancies, except adequately 
treated non-melanoma skin cancer, curatively treated 
in-situ disease, or other solid tumors curatively treated 
with no evidence of disease for ≥ 2 years
10. Known history of brain metastases or currently active 
brain metastases
11. Uncontrolled hypertension (systolic > 160 mm Hg or 
diastolic > 100 mm Hg)
12. Clinically significant electrocardiogram (ECG)
changes 
13. Myocardial infarction within 1 year before enrollment, 
symptomatic congestive heart failure (New York Heart 
Association >Class II), unstable angina, or unstable 
cardiac arrhythmia requiring medication
14. Platinum-containing drug therapy with radiotherapy
less than 6 months before study drug treatment
15. Therapeutic or palliative radiation therapy or major 
surgery within 4 weeks before study drug treatment. 
Radiation treatment to all sites of measureable disease 
unless progression is documented after radiation 
16. Participated in clinical drug trials within 4 weeks 
before study drug treatment. Current participation in 
other investigational procedures
17. Uncontrolled infection requiring intravenous (IV)
antibiotics, antivirals, or antifungals, known HIV 
infection, or active hepatitis B or C infection or 
undergoing medical treatment for infection
18. Uncontrolled type 1 or 2 diabetes mellitus 
19. Known hypersensitivity or allergic reaction against 
any of the components of the trial treatment
20. Pregnant, breastfeeding, or unwilling/unable to use 
acceptable contraception
21. Residual toxicities ≥ Grade 1 from previous therapies 
that the Investigator determines would exclude 
participation 
22. Psychological, social, familial, or geographical factors 
that would interfere with study participation or follow-
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23. Committed to an institution by virtue of an order 
issued either by judicial or administrative authorities
24. Employee or immediate relative of an employee of the 
sponsor, CRO, the study center, or their affiliates or 
partners
25. Receiving yellow fever vaccine or live attenuated 
vaccines (for subjects receiving carboplatin)
26. Presence of hemorrhagic tumors (for subjects 
receiving carboplatin)
27. Prophylactic use of phenytoin or fosphenytoin (for 
subjects receiving cisplatin or carboplatin)
Dosage Form, Dose and 
Route of Administration:
Patritumab 
 
 
  
Placebo lyophilisate will be diluted in an identical manner in 8 
mL water.
The order of IV administration will be: 
1.
Patritumab or placebo

Patritumab/placebo initial loading dose 
 
over 60 minutes (± 10 minutes)
followed in cycle 2 and beyond with a 
maintenance dose of 
 over 60 minutes 
(± 10 minutes) every three weeks

Infusion time can be extended to a maximum 
of 120 minutes for subjects unable to tolerate 
the 60 minute infusion
2.
Cetuximab 

Cetuximab initial dose at 400 mg/m2 IV as a 2-
hour infusion on Week 1, followed by 250 mg/m2
over 60 minutes weekly, plus
One hour after the end of the cetuximab administration infuse 
with either:
3.
Cisplatin OR carboplatin selected at the discretion of 
the Investigator. 

Cisplatin at 100 mg/m2 IV infused over 1 hour, 
every three weeks up to a maximum of 6 cycles

Pretreatment hydration with 2 liters of fluid 
prior to a cisplatin infusion is recommended 
and should adhere to institutional standards.  


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Adequate hydration and urinary output must 
be maintained during the following 24 hours. 
Other pretreatments such as anti-emetic 
prophylaxis and post-treatments such as 
hydration are up to the discretion of the 
Investigator. 
OR

Carboplatin, at AUC 5 IV bolus over 30 to 60 
minutes, every 3 weeks for a maximum of 6 
cycles. The carboplatin dose will be calculated 
using the Calvert formula:

AUC 5 is the target

Carboplatin Dose (mg) = 5 x ([glomerular 
filtration rate] GFR + 25)

Estimated serum creatinine clearance 
(mL/min) calculated using the modified 
Cockcroft-Gault equation (Appendix 17.1) can 
also be used as an estimate for GFR

The carboplatin dose is required to be re-
calculated for every dosing based on the 
current GFR (or creatinine clearance as an 
estimate of GFR as per the protocol)

Pre- and post-treatments are up to the 
discretion of the investigator
Note: It is important to use the infusion times given above for 
cisplatin and carboplatin; however, different infusion durations 
may be used if local practice dictates otherwise, except during 
Cycle 1, Day 1 for those subjects participating in the Intense 
PK sampling.
Commercial supplies of cetuximab, cisplatin, and carboplatin 
(if used) will be used. 
Study Endpoints:
Primary Endpoint
The primary efficacy endpoint is PFS, defined as the time from 
the date of randomization to the earlier of the dates of the first 
objective documentation of radiographic disease progression 
(per RECIST v1.1 as assessed by investigator) or death due to 
any cause.
Secondary Endpoints

OS


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
Date of randomization to death due to any 
cause

Subjects alive at time of data cut off for OS 
analysis will be censored at the last contact 
date at which subject is known to be alive

ORR (CR and PR)

Proportion of subjects with the best ORR of 
CR or PR regardless of whether it is 
confirmed or unconfirmed

Pharmacokinetic parameters: AUC0-t and Cmax at 
end of infusion (EOI) for serum patritumab, 
cetuximab, and platinum concentrations in a 
subgroup (approximately 30 subjects). 

Population PK methods will be used to assess 
the sparse data for serum patritumab 
concentrations

Safety

Treatment-emergent adverse events

≥Grade 3 National Cancer Institute Common 
Terminology Criteria for Adverse Events 
version 4.03

Clinical lab evaluations

Myocardial function status (assessed by 
echocardiograms or multigated acquisition 
scan )

ECGs

Vital signs

Physical exams

Human anti-humanized antibody formation
Exploratory Endpoints

Duration of response, time to response, time to 
disease progression, duration of stable disease

Explore potential exposure-response and possibly 
other biomarker relationships

Evaluate patient-reported outcomes
Statistical Analyses:
The primary efficacy endpoint is PFS. Primary analysis is the 
comparison of PFS between the patritumab arm and control 


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arm in the HRG high stratum of the full analysis set (FAS). 
The hypotheses testing to compare PFS between the 
patritumab arm versus the control arm will be performed in 
two steps. In step 1, PFS will be tested in the HRG high 
stratum of the FAS at the one-sided 0.10 significance level. If 
this test in step 1 does not reject the null hypothesis, then in 
step 2A, the PFS will be tested in the FAS at the one sided 
0.05 significance level. If the test in step 1 is rejected, then in 
step 2B, the two sided 80% confidence interval (CI) for hazard 
ratio (HR) of PFS in HRG low stratum of the FAS will be 
estimated. The results from both steps (PFS comparison in the 
HRG high stratum, and PFS comparison in the FAS or PFS 
estimate in the HRG low stratum) will be used to optimize 
future study designs.
The comparison of PFS between the patritumab arm and the 
control arm will be performed using a log-rank test stratified 
by the stratification factors at randomization. Kaplan-Meier 
methods will be used to calculate median PFS and CIs and 
generate Kaplan-Meier curves for PFS by treatment arm. 
Estimates of HR between 2 arms along with their two-sided 
80% and 95% CIs will be calculated using stratified Cox’s 
proportional hazards regression model.
Secondary efficacy variables include OS and ORR (CR and 
PR). Overall survival is defined from the date of 
randomization to death due to any cause and will be analyzed
in the same manner as PFS. Subjects who are alive at the time 
of data cut off for overall survival analysis will be censored at 
the last contact date at which the subject is known to be alive.  
ORR is defined as the proportion of subjects with the best 
overall response of CR or PR regardless of whether it is 
confirmed or unconfirmed. The differences in the ORR and OS 
between 2 arms in both the HRG high and low population will 
be presented along with two sided 80% and 95% CIs based on 
the Wilson’s score method with continuity correction.  
Safety data will be analyzed descriptively.
For the PK subgroup, serum patritumab, cetuximab, and 
platinum concentrations and PK parameters will be 
summarized using descriptive statistics and plotted as 
appropriate. To explore possible drug-drug interactions 
between patritumab plus cetuximab or cisplatin/carboplatin, 
the PK of serum cetuximab and platinum concentrations will 
be compared with and without patritumab. For all subjects, 
sparse samples for serum patritumab concentrations will be 
assessed using population PK methods. The relationship 


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between exposure and response will be explored using 
population PK modeling.


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TABLE OF CONTENTS
INVESTIGATOR AGREEMENT...................................................................................................2
PROTOCOL SYNOPSIS ................................................................................................................3
TABLE OF CONTENTS...............................................................................................................13
LIST OF TABLES.........................................................................................................................20
LIST OF FIGURES .......................................................................................................................21
LIST OF ABBREVIATIONS........................................................................................................22
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................25
1.1.
Data Summary ............................................................................................................25
1.1.1.
Investigational Product(s)...........................................................................................25
1.1.1.1.
Name...........................................................................................................................25
1.1.1.2.
Description..................................................................................................................25
1.1.1.3.
Intended Use Under Investigation ..............................................................................25
1.1.1.4.
Nonclinical Studies.....................................................................................................25
1.1.1.5.
Clinical Experience.....................................................................................................27
1.2.
Study Rationale...........................................................................................................28
1.2.1.
Epidemiology..............................................................................................................29
1.2.2.
Rationale for not Using Fluorouracil..........................................................................29
1.3.
Risks and Benefits for Study Subjects........................................................................30
1.4.
Population, Route, Dosage, Dosage Regimen, Treatment Period..............................30
1.5.
Compliance Statement, Ethics and Regulatory Compliance ......................................31
1.5.1.
Subject Confidentiality...............................................................................................31
1.5.2.
Informed Consent Procedure......................................................................................31
1.5.3.
Regulatory Compliance ..............................................................................................32
2.
STUDY OBJECTIVES AND HYPOTHESES ..........................................................33
2.1.
Study Objectives.........................................................................................................33
2.1.1.
Primary Objectives .....................................................................................................33
2.1.2.
Secondary Objectives .................................................................................................33
2.1.3.
Exploratory Objectives ...............................................................................................33
2.2.
Study Hypothesis........................................................................................................34
3.
STUDY DESIGN .......................................................................................................35
3.1.
Overall Plan ................................................................................................................35


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3.1.1.
Study Type..................................................................................................................35
3.1.2.
Treatment Groups .......................................................................................................36
3.1.2.1.
Treatment Administration...........................................................................................36
3.1.3.
Study Endpoints..........................................................................................................37
3.1.3.1.
Primary .......................................................................................................................37
3.1.3.2.
Secondary ...................................................................................................................37
3.1.3.3.
Exploratory .................................................................................................................38
3.1.4.
Duration of the Study..................................................................................................38
3.1.5.
Duration of Subject Participation ...............................................................................38
3.2.
Selection of Doses ......................................................................................................38
3.2.1.
Experimental Treatments............................................................................................38
3.2.2.
Control Treatments.....................................................................................................38
4.
STUDY POPULATION.............................................................................................39
4.1.
Enrollment ..................................................................................................................39
4.1.1.
Inclusion Criteria ........................................................................................................39
4.1.2.
Exclusion Criteria.......................................................................................................41
4.1.3.
Removal of Subjects From Therapy...........................................................................42
4.1.4.
Reasons for Discontinuation of Study Treatment.......................................................42
4.1.5.
Withdrawal Procedures...............................................................................................43
4.1.6.
Reasons for Discontinuation of Study Participation...................................................43
4.1.7.
Subject Replacement ..................................................................................................44
4.1.8.
Subject Re-screening Procedures ...............................................................................44
5.
TREATMENTS ADMINISTERED...........................................................................45
5.1.
Investigational Products..............................................................................................45
5.1.1.
Method of Assigning Subjects to Treatments and Blinding.......................................45
5.1.2.
Method of Assessing Treatment Compliance.............................................................45
5.1.3.
Labeling and Packaging..............................................................................................45
5.1.4.
Preparation..................................................................................................................45
5.1.5.
Storage ........................................................................................................................46
5.1.6.
Drug Accountability ...................................................................................................46
5.1.7.
Guidelines For Dose Modifications............................................................................47
5.1.7.1.
Dose Modification of Patritumab ...............................................................................48
5.1.7.2.
Dose Modification of Cetuximab ...............................................................................50


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5.1.7.3.
Dose Modification of Cisplatin ..................................................................................52
5.1.7.4.
Dose Modification of Carboplatin..............................................................................54
5.1.8.
Retention Samples ......................................................................................................55
5.1.9.
Emergency Unblinding...............................................................................................55
5.2.
Concomitant Medications...........................................................................................56
5.2.1.
Patritumab...................................................................................................................56
5.2.2.
Cetuximab...................................................................................................................56
5.2.3.
Cisplatin......................................................................................................................57
5.2.4.
Carboplatin .................................................................................................................57
6.
STUDY PROCEDURES............................................................................................58
6.1.
Screening ....................................................................................................................58
6.1.1.
Tissue Screening.........................................................................................................58
6.1.2.
Screening (Up to 14 Days Before the First Dose of Study Treatment 
Unless Otherwise Noted)............................................................................................58
6.1.3.
Randomization............................................................................................................59
6.2.
Treatment Period ........................................................................................................59
6.2.1.
Cycle 1: Week 1, Day 1..............................................................................................60
6.2.2.
Cycle 1: Week 1, Day 2..............................................................................................61
6.2.3.
Cycle 1: Week 1, Day 3..............................................................................................61
6.2.4.
Cycle 1: Week 2, Day 8..............................................................................................61
6.2.5.
Cycle 1: Week 3, Day 15............................................................................................61
6.2.6.
Cycle 2 and 3 ..............................................................................................................62
6.2.6.1.
Cycle 2, Day 1 ............................................................................................................62
6.2.6.2.
Cycles 2 and 3, Day 1.................................................................................................62
6.2.7.
Cycle 4 and all Subsequent Cycles, Day 1 .................................................................63
6.2.7.1.
Day 1...........................................................................................................................63
6.2.8.
Every 6 Weeks............................................................................................................63
6.2.9.
End of Study Treatment Visit (21 days after last dose)..............................................64
6.2.10.
40 Days After Last Dose.............................................................................................64
6.2.11.
Discontinuation From Study Treatment .....................................................................65
6.2.12.
Subjects Deriving Clinical Benefit.............................................................................65
6.3.
Follow-up Survival .....................................................................................................65
6.4.
Protocol Deviations ....................................................................................................65


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6.5.
Extension Phase..........................................................................................................65
7.
EFFICACY ASSESSMENTS ....................................................................................66
7.1.
Primary Efficacy Variable..........................................................................................66
7.2.
Secondary Efficacy Variable(s)..................................................................................66
7.3.
Exploratory Efficacy Variable(s)................................................................................66
8.
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS......................67
8.1.
Pharmacokinetic (PK) Variable(s)..............................................................................67
8.2.
Pharmacodynamic Variable(s)....................................................................................68
8.3.
Predictive Biomarker and Exploratory Variable(s)....................................................68
8.4.
Human Antihuman Antibodies...................................................................................68
8.5.
Pharmacogenomics.....................................................................................................69
9.
SAFETY ASSESSMENTS ........................................................................................70
9.1.
Adverse Events ...........................................................................................................70
9.2.
Safety Endpoints.........................................................................................................71
9.3.
Events of Special Interest ...........................................................................................71
9.3.1.
Combined Elevations of Aminotransferases and Bilirubin ........................................71
9.3.2.
Interstitial Lung Disease.............................................................................................71
9.4.
Definitions ..................................................................................................................71
9.4.1.
Adverse Event.............................................................................................................71
9.4.2.
Serious Adverse Event................................................................................................71
9.4.3.
AE Severity.................................................................................................................72
9.4.4.
Causality Assessment .................................................................................................73
9.4.5.
Action Taken Regarding the Study Product ...............................................................73
9.4.6.
Adverse Event Outcome.............................................................................................73
9.4.7.
Other Action Taken for Event ....................................................................................74
9.5.
Safety Reporting – Procedure for Investigators..........................................................74
9.5.1.
Notifying Regulatory Authorities, Investigators, and IRBs/IECs ..............................75
9.6.
Exposure In Utero During Clinical Studies................................................................75
9.7.
Clinical Laboratory Evaluations.................................................................................75
9.8.
Vital Signs ..................................................................................................................76
9.9.
Electrocardiograms.....................................................................................................76
9.10.
Physical Findings........................................................................................................76
9.11.
Other Safety Assessments...........................................................................................76


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9.11.1.
Echocardiograms or MUGA (LVEF Assessment) .....................................................76
9.11.2.
Human Antihuman Antibodies...................................................................................76
10.
OTHER ASSESSMENTS ..........................................................................................77
10.1.
Eastern Cooperative Oncology Group Performance Status........................................77
10.2.
Patient-Reported Outcomes........................................................................................77
10.2.1.
Functional Assessment of Cancer Therapy—Head and Neck (FACT-
H&N) Instrument........................................................................................................77
10.2.2.
EuroQoL-5 Dimensions-5 Levels Instrument ............................................................78
11.
STATISTICAL METHODS.......................................................................................79
11.1.
Analysis Sets...............................................................................................................79
11.1.1.
Full Analysis Set.........................................................................................................79
11.1.2.
Per-Protocol Analysis Set...........................................................................................79
11.1.3.
Safety Analysis Set.....................................................................................................79
11.2.
General Statistical Considerations..............................................................................79
11.3.
Study Population Data................................................................................................80
11.4.
Efficacy Analyses .......................................................................................................80
11.4.1.
Primary Efficacy Analyses .........................................................................................80
11.4.2.
Secondary Efficacy Analyses .....................................................................................81
11.4.3.
Exploratory Efficacy Analyses...................................................................................81
11.5.
Pharmacokinetic/Pharmacodynamic Analyses...........................................................81
11.5.1.
Pharmacokinetic Analyses..........................................................................................81
11.5.2.
Pharmacodynamic Analyses.......................................................................................82
11.5.3.
Biomarker and Exploratory Analyses.........................................................................82
11.6.
Safety Analyses ..........................................................................................................82
11.6.1.
Adverse Event Analyses.............................................................................................82
11.6.2.
Clinical Laboratory Evaluation Analyses...................................................................83
11.6.3.
Vital Sign Analyses ....................................................................................................83
11.6.4.
Electrocardiogram Analyses.......................................................................................83
11.6.5.
Physical Finding Analyses..........................................................................................83
11.6.6.
Other Safety Analyses ................................................................................................83
11.7.
Other Analyses............................................................................................................84
11.7.1.
Patient Reported Outcomes ........................................................................................84
11.7.2.
Eastern Cooperative Oncology Group........................................................................84


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11.8.
Interim Analyses.........................................................................................................84
11.9.
Data Monitoring Committee.......................................................................................84
11.10.
Sample Size Determination ........................................................................................85
12.
DATA INTEGRITY AND QUALITY ASSURANCE..............................................86
12.1.
Monitoring and Inspections........................................................................................86
12.2.
Data Collection...........................................................................................................86
12.3.
Data Management.......................................................................................................87
12.4.
Study Documentation and Storage .............................................................................87
12.5.
Record Keeping ..........................................................................................................88
13.
FINANCING AND INSURANCE.............................................................................89
13.1.
Finances ......................................................................................................................89
13.2.
Reimbursement, Indemnity, and Insurance ................................................................89
14.
PUBLICATION POLICY ..........................................................................................90
15.
STUDY ADMINISTRATIVE INFORMATION.......................................................91
15.1.
Protocol Amendments ................................................................................................91
15.2.
Address List................................................................................................................91
15.2.1.
Sponsor .......................................................................................................................91
15.2.1.1.
Sponsor Medical Monitor...........................................................................................91
15.2.1.2.
Sponsor Clinical Operations Delivery Lead...............................................................91
15.2.1.3.
CRO Medical Monitor................................................................................................92
15.2.1.4.
CRO Project Manager.................................................................................................92
15.2.1.5.
Drug Safety.................................................................................................................92
15.2.2.
Sponsor .......................................................................................................................92
15.2.2.1.
Data Management.......................................................................................................92
15.2.2.2.
Biological Specimens .................................................................................................93
15.2.2.3.
Interactive Web/Voice Response System (IxRS).......................................................93
15.2.2.4.
Pharmacogenomics Laboratory ..................................................................................93
15.2.2.5.
Bioanalytical Laboratory (PK and HAHA) ................................................................93
16.
REFERENCES ...........................................................................................................94
17.
APPENDICES ............................................................................................................97
17.1.
Modified Cockcroft-Gault Equation...........................................................................97
17.2.
Patient-Reported Outcomes........................................................................................98


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17.2.1.
Functional Assessment of Cancer Therapy-Head and Neck (FACT-
H&N)..........................................................................................................................98
17.2.2.
EuroQoL-5D-5L Health Questionnaire ....................................................................102
17.3.
Assessment of Tumor Response...............................................................................106
17.3.1.
Measurement of Tumor at Baseline..........................................................................106
17.3.1.1.
Definitions ................................................................................................................106
17.3.1.2.
Specifications by Methods of Measurements...........................................................107
17.3.2.
Tumor Response Evaluation.....................................................................................108
17.3.2.1.
Assessment of Overall Tumor Burden and Measurable Disease..............................108
17.3.2.2.
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions..............................108
17.3.2.3.
Response Criteria......................................................................................................109
17.3.2.4.
Evaluation of Target Lesions....................................................................................109
17.3.2.5.
Evaluation of Non-Target Lesions............................................................................110
17.3.2.6.
New Lesions .............................................................................................................110
17.3.2.7.
Evaluation of Best Overall Response .......................................................................111
17.3.2.8.
Frequency of Tumor Re-evaluation..........................................................................113
17.4.
Schedule of Events ...................................................................................................114


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LIST OF TABLES
Table 4.1: Criteria for Permanently Discontinuing Study Drug for Elevations of 
Aminotransferase and/or Bilirubin .............................................................................43
Table 5.1: Patritumab Maintenance Dose Modification for Toxicities .......................................48
Table 5.2: Dose Delays/Reductions for Toxicities Related to Patritumab ..................................49
Table 5.3: Cetuximab Dose Modifications..................................................................................51
Table 5.4: Cetuximab Dose Modification Guidelines for Acneiform Rash ................................52
Table 5.5: Cisplatin Dose Modifications and Discontinuations* for Toxicities..........................53
Table 5.6: Carboplatin Dose Modification for Toxicities............................................................55
Table 8.1: Sparse PK Assessments (Patritumab Only) for All Subjects......................................67
Table 8.2: Sub Study: Intensive PK Assessments Relative to the Start of 
Patritumab Infusion at Cycle 1 [n = 30] .....................................................................67
Table 10.1: Eastern Cooperative Oncology Group Performance Status Scale 
Grade Description.......................................................................................................77
Table 17.1: Time Point Response: Subjects With Target (+/–Non-Target) Disease...................112
Table 17.2: Schedule of Events for Main Study..........................................................................115
Table 17.3: Schedule of Events for Extension Phase ..................................................................118


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LIST OF FIGURES
Figure 1.1: Growth Inhibition of FaDu Head and Neck Tumors with Patritumab 
Alone or in Combination with Cetuximab, Cisplatin, or Carboplatin........................27
Figure 3.1: Phase 2 Study Design .................................................................................................35
Figure 3.2: Order and Timing of Treatments................................................................................37


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LIST OF ABBREVIATIONS
ABBREVIATION
DEFINITION
5-FU
5-Fluorouracil
AE
Adverse Event
ALT
Alanine aminotransferase
AKT
phosphatidylinositol 3-kinase /protein kinase B 
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC 
Area under the curve 
AUC0-21d
Area under concentration–time curve to Day 21
CBC
Complete blood count
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CI
Confidence intervals
Cmax
Maximum observed circulating concentration
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events 
DMC
Data Monitoring Committee
eCRF
Electronic case report form
ECG
Electrocardiograph
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
EOI
End of infusion
EQ-5D-5L
EuroQoL-5 Dimensions -5 Levels
EQ VAS
EuroQoL Visual Analogue Scale
ERK
Extracellular-signal-regulated kinases
FACT-H&N
Functional Assessment of Cancer Therapy—Head and Neck
FAS
Full analysis set
FDA
Food and Drug Administration
FHNSI
FACT—Head and Neck Symptom Index


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ABBREVIATION
DEFINITION
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
HAHA
Human antihuman antibody
HER
Human epidermal growth factor receptor
HER3
Human epidermal growth factor receptor 3
HER4
Human epidermal growth factor receptor 4
HNS
Head and neck subscale
HPV
Human papilloma virus
HR
Hazard ratio
HRG
Heregulin (product neuregulin-1 gene [nRG1])
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent ethics committee
IgG1
Immunoglobulin G subclass 1
ILD
Interstitial lung disease
IRB
Institutional review board
IV
Intravenous
IxRS
Interactive Web/Voice Response System
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MUGA
Multigated acquisition (scan)
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression free survival
PGx
Pharmacogenomics
PK
Pharmacokinetic or pharmacokinetics
PR
Partial response


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ABBREVIATION
DEFINITION
PRO
Patient reported outcome
QTc (QTcB; QTcF)
Heart rate-corrected QT interval (by Bazett’s; by Fridericia’s) 
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious adverse event
SAP
Statistical analysis plan
SAVER
Serious adverse event report
SCCHN
Squamous cell carcinoma of the head and neck
SOP
Standard operating procedure
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal


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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Data Summary
1.1.1.
Investigational Product(s)
Patritumab (U3-1287)
1.1.1.1.
Name
Patritumab
1.1.1.2.
Description
Patritumab is a high-affinity, fully human monoclonal immunoglobulin G subclass 1 
(IgG1) antibody directed against human epidermal growth factor receptor 3 (HER3).
1.1.1.3.
Intended Use Under Investigation
This study will examine patritumab’s effect on heregulin (HRG) expressing head and 
neck tumors in recurrent or metastatic squamous cell carcinoma of the head and neck 
(SCCHN).
1.1.1.4.
Nonclinical Studies
Flow cytometry analysis of Chinese hamster ovary (CHO) cells engineered to express 
individual HER family members demonstrated that patritumab specifically binds the 
extracellular domain of HER3 and did not bind to epidermal growth factor receptor 
(EGFR), HER2, or HER4. 
The binding affinity of patritumab to endogenous HER3 expressed on human tumor cells 
was 1 nmol/L to 4 nmol/L as determined in melanoma, breast cancer, and pancreatic 
cancer cells. These affinities are comparable to marketed anticancer antibodies such as 
trastuzumab and should allow for efficient targeting of HER3 on tumor cells. 
In Western blot analysis of head and neck cancer cell lines, patritumab clearly reduced 
HER3- and phosphatidylinositol 3-kinase/protein kinase B (AKT)-phosphorylation in 11 
and 10 out of 11 cell lines, respectively. Cetuximab reduced extracellular-signal-
regulated kinases (ERK)-phosphorylation in 8 out of 11 cell lines. Combinatorial effects 
of patritumab and cetuximab were seen in 8 out of 11 cell lines and in 3 out of 3
cetuximab-resistant head and neck cancer cell lines patritumab exerted inhibitory effects. 
In FaDu head and neck cancer cells, patritumab treatment resulted in inhibition of basal 
HER3 and AKT activation, whereas cetuximab treatment resulted in inhibition of basal 
ERK activation and the combination of both mAbs resulted in inhibition of HER3-, AKT-
and ERK-activation.
Treatment of FaDu and Cal-27 head and neck cancer cells with patritumab resulted in a 
reduction of proliferation ranging from 9% to 23% whereas treatment with cetuximab 
resulted in 35% to 54% inhibition of proliferation. In both cell lines, the combination of 


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patritumab and cetuximab caused a substantial stronger inhibition of proliferation (68% 
to 83%) than either single agent treatment alone.1,2
Mice with subcutaneous FaDu head and neck tumors demonstrated greater reduced tumor 
volumes when treated with patritumab 0.75 mg/kg in combination with either cetuximab, 
cisplatin, or carboplatin intraperitoneally compared to treatment with either drug alone 
(Figure 1.1).
The mean steady-state pre-infusion concentration (Cmin) at the 9 mg/kg dose level or 
above in humans was at least 5-fold greater than the threshold concentration determined 
from PK and pharmacodynamic modeling in nonclinical tumor xenograft studies and 
resulted in 90% maximal phosphorylated-HER3 inhibition and maximal nonclinical 
efficacy. Therefore, the patritumab PK profile supports intravenous (IV) administration 
of patritumab at or above 9 mg/kg every 2 to 3 weeks. Furthermore, as PK analysis 
indicated that in subjects treated with 9, 14, or 20 mg/kg every 2 weeks, steady-state was 
reached after approximately 3 doses, it is likely that a dose de-escalation to 6 mg/kg after 
initial loading dose of 18 mg/kg, followed by 9 mg/kg maintenance would still be in the 
range of the threshold concentration determined from PK and pharmacodynamic 
modeling in nonclinical tumor xenograft studies.


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Figure 1.1:
Growth Inhibition of FaDu Head and Neck Tumors with Patritumab 
Alone or in Combination with Cetuximab, Cisplatin, or Carboplatin
Please refer to the current Investigator’s Brochure for patritumab for nonclinical data 
supporting its use in clinical studies.
1.1.1.5.
Clinical Experience
A multicenter Phase 1b study, U3-1287-A-U106, was designed to evaluate patritumab in 
combination with cetuximab plus platinum-based therapy as first-line therapy for subjects 
with recurrent or metastatic SCCHN. The main objectives were to define the safety, 
tolerability, and recommended phase 2 dose of patritumab. The recommended phase 2 
dose was determined to be a loading dose of 18 mg/kg by continuous IV infusion over 
60 minutes (± 10 minutes) followed by maintenance dose of 9 mg/kg once every three 
weeks. There were no dose limiting toxicities in the subjects evaluated for safety and 
recommended Phase 2 dose. This dose of patritumab in combination with cetuximab and 
a platinum agent is the same as the established dose of patritumab in combination with 


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other therapies, including erlotinib in non-small cell lung cancer (NSCLC) and 
trastuzumab and paclitaxel in HER2-postive breast cancer.
Previously reported PK results for patritumab (using a new manufacturing process) at a 
dose of 18 mg/kg were similar to another Phase 1 study where the mean AUC0-21d and 
Cmax were observed as 3056.5 µg·day/mL and 526.0 µg/mL, respectively.1
As of 01 September 2014, 6 clinical studies have been completed. From completed 
studies the following pharmacology, efficacy, and safety results are reported below. More 
detailed information from these studies can be found in Section 6 of Investigator 
brochure. 
Clinical Pharmacology
Key clinical pharmacology results from completed studies are presented below and can 
be found in the Investigator Brochure.

The current pharmacokinetic (PK) data for patritumab (Process 2) support the 
dosing regimen of a patritumab 18-mg/kg loading dose and 9 mg/kg 
administered every 3 weeks as the maintenance dose

Population PK analyses to date suggest no apparent effect of hepatic or renal 
impairment on patritumab PK

To date, there has been low incidence of HAHA (≤ 1%) and no report of acute 
hypersensitivity reaction to patritumab1
Efficacy
Key efficacy results from completed studies can be found in the Investigator Brochure.
Safety
Key safety results from completed studies can be found in the Investigator Brochure.
Diarrhea and vomiting have been identified as adverse drug reactions associated with 
patritumab. These events are mostly Grade 1 or 2. 
1.2.
Study Rationale
HER3 is a type 1 transmembrane glycoprotein expressed in many normal tissues and in a 
variety of solid tumors including NSCLC, breast cancer, colon cancer and ovarian cancer. 
HER3 is up-regulated in many solid tumors including head and neck cancer and is 
generally associated with poor prognosis in cancer patients.3
Elevated membranous 
HER3 expression was shown to be strongly associated with poor prognosis in patients 
with SCCHN and therefore is a potential candidate molecule for targeted therapy.3
There is growing evidence that the presence of HRG, a soluble secreted growth factor, 
determines disease progression and patient survival. Heregulin is a natural ligand for 
HER3 whose binding to the extracellular domain accelerates heterodimer formation and, 
as a consequence, HER3 activation and downstream signaling. High expression 
frequencies of HRG have been demonstrated in head and neck tumor cell lines and 
clinical samples. In a panel of 15 in vivo tumor models of different tissue origin, HRG 
protein expression was found to be predictive of single-agent patritumab activity.4


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Patritumab (U3-1287) is an internalizing anti-HER3 monoclonal antibody that competes 
with HRG for receptor binding and thus is capable of inhibiting HRG-mediated HER3 
activation in vitro and in vivo. In 10/11 head and neck tumor cell lines patritumab 
inhibited basal HER3 and/or AKT activation in vitro. Synergistic effects of patritumab 
with cetuximab on signaling were seen in 7/10 (70%) patritumab-responsive head and 
neck cancer cell lines.5
Given that HRG-induced stimulation appears to play a critical role in the progression of 
HER3-expressing head and neck tumors, an antibody that blocks HER3-dependent 
oncogenic signaling, such as patritumab, may inhibit tumor cell survival, proliferation, 
and metastasis and may overcome resistance against anti-HER therapeutic agents. The 
proposed trial design in SCCHN with patritumab plus cetuximab plus platinum 
chemotherapy is a randomized study to test whether heregulin high-expressing tumors 
demonstrate better response versus the whole population in subjects with recurrent or 
metastatic squamous cell carcinoma of the head and neck.
Given the results from the Shames et al 20133 study demonstrating a significant HRG
expression increase in the recurrent setting compared to primary disease in matched 
patient specimens, it is mandatory to obtain tissue at the diagnosis of recurrent/metastatic 
SCCHN.
Patients with human papilloma virus (HPV) positive status will be included. Molecular 
and epidemiological studies strongly suggest HPV-positive oropharyngeal cancers 
comprise a distinct molecular, clinical, and pathologic disease entity that is likely 
associated with HPV infection and for which SCCHN patients who are HPV positive
have a markedly improved prognosis. In addition, it has been shown that other SCCHN 
subtypes have been found to be p16 (surrogate for HPV) positive such as nasopharyngeal, 
hypopharyngeal, laryngeal, and in the oral cavity.6 Therefore, HPV status or p16 will be 
evaluated in all tumor tissue in this study.
1.2.1.
Epidemiology
Worldwide, more than half a million head and neck cancer cases and more than 370,000 
deaths due to head and neck cancer are estimated to occur each year. The half million 
cases are comprised of approximately 300,000 oral cavity cancers, 229,000 pharyngeal 
cancers, and 157,000 laryngeal cancers.7 In 2002, the crude incidence rates of carcinoma 
of the head and neck in Europe were 36/100,000/year in the male population and 
7/100,000/year for females. Corresponding mortality rates were 18 and 3/100, 000/year, 
respectively. On the European scale, head and neck cancer accounts for 139,000 new 
cases per year. Over 90% of head and neck malignancies are squamous cell carcinomas.8
1.2.2.
Rationale for not Using Fluorouracil
The combination of cetuximab and cisplatin plus fluorouracil (5-FU) is approved for 
first-line treatment of SCCHN in countries worldwide.9
With respect to efficacy, 
therapeutic regimens are used for SCCHN with or without 5-FU. Few studies have 
demonstrated that 5-FU has provided progression free survival (PFS) or overall survival 
(OS) advantage compared to combinations without 5-FU.10 With respect to safety, 5-FU 


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used in combination with other drugs in SCCHN and other indications have been 
associated with increased toxicities.11,12,13
In a Phase 3 study11 in advanced head and neck cancer, it was found that the 5-FU plus 
cisplatin group had more toxicities overall than subjects in the cisplatin plus paclitaxel 
group, especially in leukopenia, granulocytopenia, thrombocytopenia, anemia, infection, 
genitourinary, vomiting, stomatitis, metabolic disorders, and fatigue. In a Phase 3 
randomized study in SCCHN,12 a comparison was made between cisplatin plus 5-FU 
versus 5-FU alone and cisplatin alone.  It was found that, in general, toxicities were 
higher in the 5-FU alone and in the cisplatin plus 5-FU combination arm, compared to the 
cisplatin alone group.  The increased toxicities in the 5-FU alone and 5-FU plus cisplatin 
arms included diarrhea, mucositis, ototoxicity, phlebitis, alopecia, and leukocytosis. 
Tribius et al conducted a study in locally advanced unresectable stage IV SCCHN 
comparing courses of cisplatin and cisplatin plus 5-FU and found that the regimen 
containing cisplatin alone had 46% grade 3 toxicities and the regimen containing cisplatin 
and 5-FU had 70% grade 3 toxicities.13 . In summary of the above mentioned studies, the 
safety profile of regimens using 5-FU has generally shown a high percentage of toxicities 
which include anemia, neutropenia, mucositis, diarrhea and thrombocytopenia. 
Administration of 5-FU is also inconvenient because it requires a continuous infusion 
pump, with infusions of 12-24 hours for 4-5 consecutive days. In addition, the quality of 
life of head and neck cancer patients without infusion pumps is significantly better 
compared to those using infusion pumps.14
The safety data of studies in SCCHN with and without 5-FU demonstrated that 5-FU is 
associated with increased toxicities as well as reduced quality of life.  Given the very 
modest efficacy benefits associated with 5-FU, the benefit-risk ratio of 5-FU-containing 
cetuximab plus platinum regimens is not clearly superior to that of similar regimens 
without 5 FU.
1.3.
Risks and Benefits for Study Subjects
Patritumab is an investigational anti-HER3 antibody with demonstrated preclinical and 
early clinical activity as a single agent and in combination with other chemotherapies.  
The toxicities of approved HER family antibody inhibitors may not be predictive of 
toxicity for patritumab due to differing antibody and target specificity.  The most 
significant adverse reactions identified with patritumab use are diarrhea, vomiting, rash, 
and dry skin.  However, administration of some therapeutic antibodies has been 
associated with infusion or allergic reactions.  Subjects receiving patritumab should be 
monitored for these reactions.
1.4.
Population, Route, Dosage, Dosage Regimen, Treatment Period
Adult subjects with metastatic SCCHN originating from the oral cavity, oropharynx, 
hypopharynx, and larynx, with documented disease recurrence following previous 
treatment regimen for non-metastatic disease will be studied. See Section 4 for a detailed 
description of the study population.  See Section 3.1.2 for information regarding route, 
dosage, and dosage regimen, and Section 3.1.5 for information on the duration of the 
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1.5.
Compliance Statement, Ethics and Regulatory Compliance
This study will be conducted in compliance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki (2013), the International Conference on 
Harmonization (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) 
(Committee for Proprietary Medicinal Products/ICH/135/95), and applicable regulatory 
requirement(s).

European Commission Directive (2001/20/EC Apr 2001) and/or

European Commission Directive (2005/28/EC Apr 2005) and/or

Food and Drug Administration (FDA) GCP Regulations: Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or

Other applicable local regulations 
1.5.1.
Subject Confidentiality
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking 
part in the study, in accordance with GCP and local regulations.
The Investigator must ensure that the subject’s anonymity is maintained.  On the 
electronic Case Report Forms (eCRF) or other documents submitted to the Sponsor 
and/or agent, subjects should be identified by a unique subject identifier as designated by
the sponsor.  Documents that are not distributed (eg, signed Informed Consent Forms 
[ICF]) should be kept in strict confidence by the Investigator.
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB) direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  The Investigator is obligated to inform 
the subject that his/her study-related records will be reviewed by the above named 
representatives without violating the confidentiality of the subject.
1.5.2.
Informed Consent Procedure
Before a subject’s participation in the study, it is the Investigator’s responsibility to 
obtain freely given consent, in writing, from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any study drugs are administered.  The written 
ICF should be prepared in the local language(s) of the potential subject population and 
documented in the subject’s medical records, as required by 21 CFR Part 312.62.
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki.  The consent form and any 
revision(s) should be approved by the IEC or IRB prior to being provided to potential 
subjects.


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The ICF should be signed and personally dated by the subject, and by the person who 
conducted the informed consent discussion (not necessarily the Investigator).  The 
original signed ICF should be retained in accordance with institutional policy, and a copy 
of the signed consent form should be provided to the subject or legal representative.  The 
date and time (if applicable) that informed consent was given should be recorded on the 
case report form (CRF).
1.5.3.
Regulatory Compliance
The study protocol, subject information and consent form, the Investigator brochure, any 
subject diary card or written instructions to be given to the subject, available safety 
information, subject recruitment procedures (eg, advertisements), information about 
payments and compensation available to the subjects, and documentation evidencing the 
Investigator’s qualifications should be submitted to the IEC or IRB for ethical review and 
approval according to local regulations, prior to the study start.  The written approval 
should identify all documents reviewed by name and version.
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the Statistical Analysis Plan (SAP).
The Investigator must submit and, where necessary, obtain approval from the IEC or IRB
for all subsequent protocol amendments and changes to the informed consent document 
or changes of the investigational site, facilities or personnel.  The Investigator should 
notify the IEC or IRB of deviations from the protocol or serious adverse events (SAEs)
occurring at the site and other adverse event (AE) reports received from Daiichi Sankyo 
and/or Contract Research Organization (CRO), in accordance with local procedures.
Daiichi Sankyo’s Regulatory Affairs group will ensure that approval by the appropriate 
regulatory bodies is obtained prior to study initiation and that implementation of changes 
to the initial protocol and other relevant study documents happen only after the 
appropriate notification of or approval by the relevant regulatory bodies.


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2.
STUDY OBJECTIVES AND HYPOTHESES
2.1.
Study Objectives
2.1.1.
Primary Objectives

To evaluate PFS in the HRG high expression population from subjects treated 
with patritumab + cetuximab + platinum-based therapy compared to placebo + 
cetuximab + platinum-based therapy
2.1.2.
Secondary Objectives

Evaluate OS 

Evaluate objective response rate (ORR) 

Refine the cutoff between HRG high and low expression based on clinical 
data from this study

Assess the population PK of patritumab in subjects with SCCHN

Assess the PK parameters of serum cetuximab and platinum concentrations 
when cetuximab and cisplatin or carboplatin (platinum-based therapy) are 
coadministered with patritumab in a subgroup (n = 30) of subjects

Evaluate the incidence of HAHA formation (anti-patritumab antibodies)

Evaluate the safety and tolerability of the combination of patritumab + 
cetuximab + platinum-based therapy in first-line treatment of subjects with 
SCCHN
2.1.3.
Exploratory Objectives

Duration of response, time to response, time to disease progression, duration 
of stable disease (SD) from subjects treated with patritumab + cetuximab + 
platinum-based therapy compared to those treated on placebo + cetuximab + 
platinum-based therapy

Explore potential exposure-response and possibly other biomarker 
relationships

Evaluate disease specific patient reported outcomes (PROs) using the 
Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) 
which assesses:

Physical well-being

Functional well-being

Social/Family well-being

Emotional well-being


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
Head and neck cancer symptoms

Evaluate head and neck cancer symptoms using the FACT-Head and Neck 
Symptom Index (FHNSI), a 10-item instrument comprising items from the 
FACT-H&N

Evaluate PROs using the EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) 
questionnaire, which assesses five dimensions:

Mobility 

Self-care

Usual activities 

Pain/discomfort

Anxiety/depression (See Appendix 17.2).
2.2.
Study Hypothesis

The combination of patritumab + cetuximab + platinum-based therapy will 
improve PFS in the first-line treatment of SCCHN in the HRG high 
expression population compared to subjects in the placebo + cetuximab + 
platinum-based arm


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3.
STUDY DESIGN
3.1.
Overall Plan
Approximately 105 subjects will be randomized to the patritumab and the control arms in 
2:1 stratification fashion between HRG high versus low strata (approximately 70 
HRG-high and approximately 35 HRG-low subjects). When one HRG stratum is filled 
with the required sample size, the enrollment in that HRG stratum will cease. The 
randomized subjects will also be further stratified 1:1 by HPV status (positive vs 
negative). The cut-off for HRG high versus low before randomization will be set using 
the median HRG value of commercial tissue samples. See Figure 3.1 for a schematic of 
the study design.
Figure 3.1:
Phase 2 Study Design
3.1.1.
Study Type
This is a multicenter, randomized, placebo-controlled, double blind Phase 2 study 
designed to evaluate the PFS and safety in recurrent/metastatic first-line SCCHN in 
subjects treated with patritumab plus cetuximab plus either cisplatin or carboplatin or 
randomized to the control arm consisting of a placebo plus cetuximab plus either cisplatin 
or carboplatin.
Adult subjects with metastatic SCCHN originating from the oral cavity, oropharynx, 
hypopharynx, and larynx with documented disease recurrence following previous 
treatment for non-metastatic disease will be studied. 


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3.1.2.
Treatment Groups
There will be two treatment arms (See Figure 3.1) stratified by HRG status (high and 
low).
1. Patritumab + cetuximab + platinum-based therapy with HRG high and HRG 
low subjects
2. Placebo + cetuximab + platinum-based therapy with HRG high and HRG low 
subjects
3.1.2.1.
Treatment Administration
Figure 3.2 illustrates the order and timing of the treatments involved.

Patritumab initial loading dose is 18 mg/kg IV (or placebo) over 60 minutes 
(± 10 minutes) followed in cycle 2 and beyond with a maintenance dose of 9 
mg/kg IV over 60 minutes (± 10 minutes) every three weeks

Infusion time can be extended to a maximum of 120 minutes for subjects 
unable to tolerate the 60 minute infusion

Cetuximab initial dose at 400 mg/m2 IV as a 2-hour infusion followed by 
250 mg/m2 over 60 minutes weekly 
One hour after the end of the cetuximab administration (on the weeks when 
cetuximab and platinum therapy are coadministered) infuse with either:

Cisplatin at 100 mg/m2 IV infused over 1 hour, every three weeks up to a 
maximum of 6 cycles

Pretreatment hydration with 2 liters of fluid prior to a cisplatin infusion is 
recommended and should adhere to institutional standards.  Adequate 
hydration and urinary output must be maintained during the following 
24 hours. Other pretreatments such as anti-emetic prophylaxis and post-
treatments such as hydration are up to the discretion of the Investigator 

This can be given in a separate infusion during patritumab and cetuximab 
infusion
OR

Carboplatin, IV bolus over 30-60 minutes, every 3 weeks for a maximum of 
6 cycles. The carboplatin dose will be calculated using the Calvert formula:

AUC 5 is the target

Carboplatin Dose (mg) = 5 x (glomerular filtration rate [GFR] + 25)

Estimated serum creatinine clearance (mL/min) calculated using the 
modified Cockcroft-Gault equation (Appendix 17.1) can also be used as 
an estimate for GFR


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
The carboplatin dose is required to be re-calculated for every dosing based
on the current GFR (or creatinine clearance as an estimate of GFR as per 
the protocol).

Pre- and post-treatments are up to the discretion of the investigator
Note: It is important to use the infusion times given above for cisplatin and carboplatin; 
however, different infusion durations may be used if local practice dictates otherwise,
except during Cycle 1, Day 1 for those subjects participating in the Intense PK sampling.
Figure 3.2:
Order and Timing of Treatments
3.1.3.
Study Endpoints
3.1.3.1.
Primary

PFS in the HRG high expression population from subjects treated with 
patritumab + cetuximab + platinum-based therapy compared to placebo + 
cetuximab + platinum-based therapy
3.1.3.2.
Secondary

OS 

ORR 

PK parameters of serum cetuximab and platinum concentrations when 
cetuximab and cisplatin or carboplatin are coadministered with patritumab in a 
subgroup (n=30) of subjects

Population PK of patritumab 

Incidence of HAHA formation (anti-patritumab antibodies)

Safety and tolerability of the combination of patritumab + cetuximab + 
platinum-based therapy in first-line treatment of subjects with SCCHN


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3.1.3.3.
Exploratory

Duration of response

Time to response

Time to disease progression 

Duration of SD in both HRG groups

Explore potential exposure-response and possibly other biomarker 
relationships

Evaluation of PROs
3.1.4.
Duration of the Study
For the purpose of collecting survival data, the duration of the study will be until all 
subjects have died or a minimum of 13 months after the last subject is randomized 
whichever comes first, approximately 22 months for PFS and 25 months for OS.
3.1.5.
Duration of Subject Participation
The screening period is up to 14 days. Each cycle of treatment will be 21 days. There is 
no limit to how many cycles for patritumab and cetuximab treatment. Treatment will 
continue without interruption in subjects with complete response (CR), partial response 
(PR), or stable disease (SD). However, platinum treatment (cisplatin or carboplatin) will 
be given up to a maximum of 6 cycles. Subject participation is expected to be 
approximately 20 months.
Subjects who benefit from therapy may continue in the extension phase (Section 6.5) to 
receive treatment until progressive disease (PD), toxicity, withdrawal of consent, or 
starting another treatment for cancer therapy.
3.2.
Selection of Doses
The dosing regimen of patritumab to be administered in this study was selected on the 
basis of efficacy and tolerability established in prior Phase 1 and Phase 2 studies. Doses 
of each of the study treatments are specified in Section 3.1.2.
3.2.1.
Experimental Treatments
Please see Section 3.1.2.
3.2.2.
Control Treatments
See Section 3.1.2.


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4.
STUDY POPULATION
4.1.
Enrollment
Each subject will be provided with information about the study, will have all questions 
answered to their satisfaction, and will sign and date an ICF. There will be individual 
ICFs for the main study, pharmacogenetics, and tissue sampling. Additional information 
about informed consent procedures is provided in Section 1.5.2.
A subject is considered enrolled in the study upon the Investigator or designee obtaining 
written informed consent from the subject (Section 1.5.2), and upon determination that all 
inclusion and exclusion criteria have been satisfied.  
Investigators will maintain a confidential screening log of all potential study candidates 
that includes limited subject information (initials, age, and sex), date, and outcome of
screening process (eg, enrollment in the study, reason for ineligibility, refused to 
participate) will be maintained.
The Investigator or designee will be expected to maintain an Enrollment Log of all 
subjects enrolled in the study indicating their assigned study number.
4.1.1.
Inclusion Criteria
Subjects must satisfy all of the following criteria to be included in the study:
1. Adult subjects ≥18 years old
2. Histologically confirmed recurrent disease or metastatic SCCHN tumor and/or 
from its lymph nodal metastases originating from the oral cavity, oropharynx, 
hypopharynx, and larynx
3. Heregulin expression level is required

Samples must be taken from subjects who have recurrent or metastatic 
disease (rec/met). These samples can be from either rec/met archived or 
fresh biopsy samples (either primary tumor or metastases)

No cancer treatment between time of biopsy and submission of sample

Surgical or core needle biopsy is acceptable

Fine-needle aspiration or cytology is not acceptable for biopsies
4. HPV status or p16 (surrogate for HPV) is required. These results must come from 
tumor tissue. These results may be obtained from either a local lab or samples 
sent to the central lab

HPV or p16 status can be from any tumor biopsy material from initial 
diagnosis
5. Measurable disease per Response Evaluation Criteria in Solid Tumor (RECIST) 
Version 1.1


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6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
7. Hematological function, as follows:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 

Platelet count ≥ 100 x 109/L

Hemoglobin ≥ 10 g/dL
8. Renal function, as follows:

Estimated serum creatinine clearance (mL/min) or GFR ≥ 60 mL/min for 
cisplatin and ≥30 mL/min for carboplatin
9. Hepatic function, as follows: 

Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) (if 
liver metastases are present, < 5 x ULN)

Alanine aminotransferase (ALT) ≤ 2.5 x ULN (if liver metastases are 
present, < 5 x ULN)

Alkaline phosphatase ≤ 2.0 x ULN (if bone or liver metastases are present,
< 5 x ULN)

Bilirubin ≤ 1.5 x ULN
10. Prothrombin time  or partial thromboplastin time ≤ 1.5 x ULN
11. Women of childbearing potential must have a negative serum pregnancy test 
performed within 14 days prior to enrollment (where demanded by local 
regulations, test may be required within 72 hours prior to enrollment)
12. Adult subjects of child-bearing potential must agree to use double-barrier 
contraceptive measures. Two of the following precautions must be used: bilateral 
vasectomy, bilateral tubal ligation, intrauterine device (IUD), combined (estrogen 
and progesterone containing) hormonal contraception associated with inhibition 
of ovulation (oral, intravaginal, transdermal), progesterone-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, 
implantable), intrauterine hormone-releasing system (IUS), condom with 
spermicide, abstinence. These contraception measures must be used for the entire 
duration of the study and for 6 months after the last study dose is received15
13. Subjects must be willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures
14. Provided written informed consent(s)


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4.1.2.
Exclusion Criteria
Subjects who meet any of the following criteria will be disqualified from entering the
study:
1. Left ventricular ejection fraction (LVEF) <50%
2. Prior EGFR targeted regimen
3. No HRG expression result
4. No HPV or p16 status
5. Prior anti-HER3 therapy
6. Prior chemotherapy for recurrent/metastatic disease
7. Anti-cancer therapy between biopsy and submission of sample
8. Presence of squamous cell tumors of the nasopharynx
9. History of other malignancies, except adequately treated non-melanoma skin 
cancer, curatively treated in-situ disease, or other solid tumors curatively treated 
with no evidence of disease for ≥ 2 years
10. Known history of brain metastases or active brain metastases
11. Uncontrolled hypertension (systolic > 160 mm Hg or diastolic > 100 mm Hg)
12. Clinically significant electrocardiograph (ECG) findings 
13. Myocardial infarction within 1 year before enrollment, symptomatic congestive 
heart failure (New York Heart Association >Class II), unstable angina, or unstable 
cardiac arrhythmia requiring medication
14. Platinum-containing drug therapy with radiotherapy less than 6 months before 
study drug treatment
15. Therapeutic or palliative radiation therapy or major surgery within 4 weeks before 
study drug treatment. Radiation treatment to all sites of measureable disease 
unless progression is documented after radiation
16. Participated in clinical drug trials within 4 weeks before study drug treatment. 
Current participation in other investigational procedures
17. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known 
HIV infection, or active hepatitis B or C infection or undergoing medical 
treatment for infection
18. Uncontrolled type 1 or 2 diabetes mellitus
19. Known hypersensitivity or allergic reaction against any of the components of the 
trial treatment
20. Pregnant, breastfeeding, or unwilling/unable to use acceptable contraception
21. Residual toxicities ≥ Grade 1 from previous therapies that the Investigator 
determines would exclude participation


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22. Psychological, social, familial, or geographical factors that would interfere with 
study participation or follow-up
23. Committed to an institution by virtue of an order issued either by judicial or 
administrative authorities
24. Employee or immediate relative of an employee of the sponsor, CRO, the study 
center, or their affiliates or partners
25. Receiving yellow fever vaccine or live attenuated vaccines (for subjects receiving 
carboplatin)
26. Presence of hemorrhagic tumors (for subjects receiving carboplatin)
27. Prophylactic use of phenytoin or fosphenytoin (for subjects receiving cisplatin or 
carboplatin)
4.1.3.
Removal of Subjects From Therapy
Any subject may withdraw from the study treatment or from the study at any time
without specifying a reason. If a subject withdraws from the study treatment or study, the 
reason for withdrawal will be recorded on the eCRF. The Investigator will complete and 
report the observations as thoroughly as possible up to the date of withdrawal including 
the date of last treatment and the reason for withdrawal.
4.1.4.
Reasons for Discontinuation of Study Treatment
Reasons for discontinuation of a subject from the study include: PD as per RECIST 1.1 or 
clinician’s assessment, AE, death, withdrawal of consent by subject, significant protocol 
violation, or sponsor decision to terminate the study.
In the event of a decision to discontinue study drug treatment the investigator will contact 
the subject directly to explain the circumstances requiring study treatment to be stopped. 
The subject will be instructed to attend the safety follow-up visit required by the study 
protocol, and the treating physician will discuss alternative treatment options with the 
subject.
The reason for discontinuation will be recorded. 
Subjects may be withdrawn from the study after signing informed consent for the 
following reasons:

Adverse Event

Lost to Follow-up

Withdrawal of Consent by Subject

Physician Decision

Death

Pregnancy

Progressive Disease


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
Study Terminated by Sponsor

Other
All subjects who are withdrawn from the study should complete protocol specified 
withdrawal procedures, unless they withdraw their consent (Section 4.1.5).
Elevations in AST/ALT and/or total bilirubin that meet the criteria described in Table 4.1
require permanent discontinuation of the subject from patritumab/placebo and cetuximab.
Table 4.1:
Criteria for Permanently Discontinuing Study Drug for Elevations of 
Aminotransferase and/or Bilirubin
Discontinuation Criteria
Confirmation Period
Serum AST or ALT > 3 x ULN and total bilirubin of > 2 x ULN
Repeat testing 3-7 days later to 
confirm laboratory results
AST or ALT > 5 x ULN
Repeat testing 3-7 days later to 
confirm laboratory results
4.1.5.
Withdrawal Procedures
If a subject withdraws from the study, the Investigator or designee will complete and 
report the observations in the eCRF as thoroughly as possible up to the date of 
withdrawal including the date of last treatment and the reason for withdrawal.
If the subject is withdrawn due to an AE, the Investigator will follow the subject until the 
AE has resolved or stabilized.
The End of Study Treatment visit will be conducted within 21 days after administration 
of the last dose of study treatment (ie, the last dose of any study drug administered).  At 
40 days after the last dose a telephone call will be placed to the subject to record AEs.
For subjects with positive anti-patritumab neutralizing antibody in the serum sample 
drawn at the End of Study Treatment visit, additional serum samples should be obtained 
every 3 months for antibody measurement until the antibody level returns to baseline (or 
becomes negative) or up to 1 year from the last dose of study drug or if the subject starts 
another therapy for their cancer, whichever occurs first.  A PK sample for patritumab will 
be collected at the time of HAHA collection for interpretation of HAHA results.
4.1.6.
Reasons for Discontinuation of Study Participation
Subjects may terminate participation with study procedures if any of the following 
occurs:

Subject withdraws consent to participate in study procedures

Subject dies

Study is terminated by sponsor

Subject is lost to follow-up


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Note: All subjects will be followed for survival status even after consent for study 
procedures is withdrawn. Subjects discontinued from the study because of withdrawal of 
consent will be followed for survival by collecting public records (eg, death certificates) 
unless prohibited by local laws. 
4.1.7.
Subject Replacement
Subjects will not be replaced in this study.
4.1.8.
Subject Re-screening Procedures
Re-screening is permitted for any subject who failed to meet reversible or transient 
eligibility criteria upon initial screening.  The subject identification number must remain 
the same at the time of re-screening.  The initial reason why the subject is ineligible for 
the initial evaluation will be recorded on the Screening Log.  No data from the initial 
evaluation will be entered into the clinical database for a subject who is re-screened.


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5.
TREATMENTS ADMINISTERED
5.1.
Investigational Products
The Investigator must ensure that the blinded investigational product (ie, patritumab) will 
be used only in accordance with the protocol, as specified in Section 3.1.2. Placebo will 
be provided in a matching vial.
The vial labels will contain a description of the contents, batch number, and where 
appropriate, storage conditions and any additional statements as required by local 
regulations.   
Daiichi Sankyo will provide carboplatin for this study. Wherever possible, commercial 
supplies of cetuximab and cisplatin will be supplied by the clinical site.
Daiichi Sankyo will only supply cetuximab and cisplatin to those sites that are not able to 
supply themselves.
5.1.1.
Method of Assigning Subjects to Treatments and Blinding
Approximately 105 subjects who have an HRG expression value and HPV status (+/-)
will be assigned randomly in a blinded manner by the Interactive Web/Voice Response 
System (IxRS) to the patritumab or the control arms in a 2:1 stratification (approximately 
70 HRG-high and approximately 35 HRG-low subjects). 
Please refer to Section 3.1 and Figure 3.1 for details.
5.1.2.
Method of Assessing Treatment Compliance
All study drugs will be administered at the study site, under the supervision of the 
Investigator or designee in accordance with the protocol, to subjects participating in the 
clinical study.  Administration of study drugs, including time of administration and dose 
administered, must be recorded in the eCRF.
5.1.3.
Labeling and Packaging
The vial label will contain a description of the contents, batch number, and where 
appropriate, storage conditions and any additional statements as required by local 
regulations.   
5.1.4.
Preparation
Patritumab will be provided as a sterile lyophilisate with 240 mg/vial to be reconstituted 
with 8 mL water for injection to obtain a concentration of 30 mg/mL patritumab solution.  
Placebo lyophilisate will be diluted in an identical manner.
Subjects will be dosed based on the previous visit’s weight.  If the subject’s weight at any 
visit has changed by ±10% from the previous visit weight, the dose will be recalculated.
Patritumab or placebo will be prepared for each subject from allocated vials. Multiple 
individually numbered vials will be allocated to the subject via the IxRS and confirmed 


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on a subject/visit vial allocation report. Allocation of vials is not possible outside the 
IxRS. Concerns may be discussed with the CRO or Sponsor.
Refer to the Pharmacy Manual for detailed information regarding the preparation and 
administration of patritumab or placebo. Cetuximab, cisplatin, and carboplatin will be 
prepared according to the package insert.
5.1.5.
Storage
Acknowledgement of drug shipments is managed through the IxRS to ensure materials 
are received in good condition before use.  Drug supplies must be stored in a secure, 
limited access storage area under the recommended storage conditions.
Patritumab or matching placebo powder must be stored in a refrigerator set between 2°C 
and 8°C, and protected from light.  Exposure to temperatures outside the recommended 
range or vigorous shaking of reconstituted drug product solution should be avoided.  
Temperature excursions outside the recommended range should be reported to the CRO 
and Sponsor. Once thawed, the product solution should not be refrozen.
Storage conditions for cetuximab, cisplatin, and carboplatin will follow respective 
labeling.
Records of the actual storage conditions during the period of the study must be 
maintained (eg, records of the date and time and the initials of the person checking, the 
“working day” temperatures of the refrigerator used for storage of trial supplies, 
continuous temperature recordings or regularly maintained temperature alarm systems 
used in conjunction with temperature recording). 
5.1.6.
Drug Accountability
When a drug shipment is received, the Investigator or designee will check the amount 
and condition of the drug, check for appropriate local language in the label, and drug 
expiration date.  The original shipment document will be retained at the site. 
A Drug Accountability Record (separate from the eCRF) will be provided for 
patritumab/placebo, cetuximab, cisplatin, and/or carboplatin if applicable. The record 
must be kept current and should contain the dates and quantities of drugs received, the 
subject’s details (ie, identification number and/or initials or supply number, as 
applicable), for whom the drug was dispensed, the date and quantity of drug dispensed, as 
well as the initials of the dispenser. 
At the end of the study, or as directed, the unused patritumab/placebo and carboplatin, if 
applicable, in addition to cetuximab and cisplatin supplies, if provided by the sponsor,
will be returned to a designee as instructed by the Sponsor.  The drug supplies will be 
returned only after the study monitor has completed a final inventory to verify the 
quantity to be returned and reconciled any discrepancies.  The return of the drug supplies 
must be documented and the documentation included in the shipment.  At the end of the 
study, a final Investigational Product reconciliation statement must be completed by the 
Investigator or designee and provided to the Sponsor.  Unused drug supplies may only be 
sent for destruction by the pharmacy, per sites’ standard operating procedures (SOPs) if 
the sites have been given permission from the sponsor in writing following SOP review. 


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If permission has not been given to destroy unused drug supplies locally they must be 
returned as instructed.
All investigational product inventory forms must be made available for inspection by a 
Sponsor’s authorized representative or designee and regulatory agency inspectors.  The 
Investigator or designee is responsible for the accountability of all used and unused study 
supplies at the site.
5.1.7.
Guidelines For Dose Modifications
For those subjects who continue treatment, the Investigator will evaluate which 
hematological and/or non-hematological toxicities are attributed to which drug(s), and 
adjust the dose of one or more of the drugs as recommended below.
If a subject experiences an unacceptable toxicity to cisplatin, the Investigator will be able 
to withhold drug, reduce dose, or switch to carboplatin.  If the Investigator chooses to 
start treatment with carboplatin, then carboplatin will be administered throughout the 
study.  If a subject also experiences an unacceptable toxicity to carboplatin, then 
carboplatin treatment will be withheld or dose reduced.
Subjects with unacceptable toxic effects of one of the study drugs will receive only the 
tolerated drugs until disease progression.

If patritumab/placebo needs to be discontinued, the subject will be withdrawn 
from the study

In subjects whose cisplatin or carboplatin therapy is discontinued, reduced, or 
delayed, the patritumab and cetuximab will be continued and subjects will 
continue to undergo tumor assessments at 6 week intervals until disease 
progression or unacceptable toxicity

In subjects whose cetuximab dose is discontinued, reduced, or delayed, the 
patritumab will be continued.  Cisplatin or carboplatin will be administered 
for a maximum of 6 cycles

In subjects whose cetuximab and cisplatin or carboplatin are either 
discontinued or delayed, patritumab will be continued as monotherapy
In addition to the recommendations provided below, please refer to the respective current 
prescribing information for detailed recommendations on managing suspected toxicities, 
for guidance on withholding, dose reductions, and discontinuation. If toxicities occur, it is 
up to the discretion of the Investigator to dose reduce or withhold one or more 
medications until recovery or resolution of the AE to Grade 0 or 1.
In individual cases, if a subject discontinues study drugs for an extended time period, the 
subject may restart study drugs at the discretion of the investigator after discussion with 
the Sponsor and CRO’s medical monitors.
Investigators may contact the Sponsor’s medical monitor to discuss any question 
regarding dose modification or discontinuation of study drugs.


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5.1.7.1.
Dose Modification of Patritumab
Patritumab is contraindicated for subjects with known hypersensitivity to either the drug 
substance or inactive ingredients in the drug product.  In previous patritumab studies, the 
most common toxicities that occurred were rash, diarrhea, vomiting, nausea, fatigue, 
dyspnea, and skin and subcutaneous tissue disorders.  Table 5.1 and Table 5.2 pertain to 
patritumab dose modifications.
If the initial loading dose of 18 mg/kg is not tolerated, infusion time can be extended to a 
maximum of 120 minutes for subjects unable to tolerate the 60 minute infusion.
Patritumab/placebo is to be withheld from a subject experiencing a CTCAE Grade 3 AE, 
and resumed at the next regularly scheduled patritumab dosing (maintenance dose of 
9 mg/kg) only after resolution of the AE to Grade 0 or 1 (or baseline grade if higher than
Grade 1). 
If a rash or mucositis occurs following the initial dose of patritumab 18 mg/kg, then hold 
the patritumab until the AE resolves to Grade 0 or 1 (or baseline grade if higher than
Grade 1). If the rash or mucositis has not resolved, then hold cetuximab 250 mg/m2 until 
the AE resolves to Grade 0 or 1 (or baseline grade if higher than Grade 1). If a rash or 
mucositis occurs on the maintenance dose of patritumab at 9 mg/kg, hold patritumab until 
the AE resolves to Grade 0 or 1 (or baseline grade if higher than Grade 1) and then 
decrease patritumab dosing to 6 mg/kg. If the AE does not resolve, hold the next dose of 
cetuximab until resolution to Grade 0 or 1 (or baseline grade if higher than Grade 1).
Left ventricular ejection fraction will be monitored throughout the study (see 
Section 9.11.1) for possible effects of patritumab treatment on cardiac function. Dose 
modification or suspension of patritumab treatment will be based on decreased LVEF, as 
outlined in Table 5.1.
For cases of ILD, refer to Section 9.3.2.
Both patritumab/placebo are to be withheld from a subject experiencing a Grade 4 AE.
Table 5.1:
Patritumab Maintenance Dose Modification for Toxicities
Toxicity
Withhold Criteria Resumption 
Criteria
Dose Reduction
Criteria
Discontinuation 
Criteria
All AEsa
Grade 3 or higher
Grade 0 or 1 (or 
baseline grade if 
higher than Grade 
1)b
Reduce patritumab 
maintenance dose 
from 9 mg/kg to 
6 mg/kg (for 
mucositis follow 
dose modification as 
defined above)
Failure to recover 
within 3 weeks


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Toxicity
Withhold Criteria Resumption 
Criteria
Dose Reduction
Criteria
Discontinuation 
Criteria
Ejection 
fraction 
Grade greater than 
or equal to 3, 
(LVEF of less than 
40% or LVEF 
decrease of more 
than 20% from the 
baseline)
LVEF of at least 
50% (or baseline) 
based on a repeat 
echocardiogram or 
MUGA scan
performed in 3 
weeks
Reduce patritumab 
maintenance dose 
from 9 mg/kg to 
6 mg/kg
LVEF that does not 
recover within 3 
weeks:
Decreased ≥ Grade 3
<40%
>20% decrease from 
baseline
a For elevations of aminotransferase (AST/ALT) and/or bilirubin, please see Section 4.1.4.
b Patritumab/placebo dosing may be resumed upon consultation with the Sponsor’s medical monitor if the 
event has resolved to Grade 2.
MUGA = multigated acquisition (scan); LVEF = left ventricular ejection fraction.
Dose delays/reductions for toxicities related to patritumab are summarized in Table 5.2.
Table 5.2:
Dose Delays/Reductions for Toxicities Related to Patritumab
Grade
Action
1
Continue current dose level
2
Continue current dose level
3
Discontinue patritumab/placebo for up to 3 weeks until the event has recovered to Grade 
1 or baseline.a Administer patritumab at a dose that is decreased by one dose level for 
subsequent cycles.  A maximum of 1 dose reduction from the 9 mg/kg IV maintenance 
dose to 6 mg/kg IV maintenance dose will be permitted. No dose reductions below 
patritumab 6 mg/kg will be allowed.   
4
Discontinue patritumab/placebo for up to 3 weeks until the event recovers to Grade 1 or 
baseline.a  Discuss the event with the sponsor’s Medical Monitor or designee before 
restarting patritumab/placebo.  If the investigator and the sponsor’s Medical 
Monitor/designee agree, the weekly maintenance dose will also be decreased from 
9 mg/kg IV to 6 mg/kg IV. 
a If the subject fails to recover to Grade 1 or baseline and dose must be delayed >3 weeks, the subject will 
be withdrawn from all study treatment, but should continue to undergo all follow-up evaluations
To receive patritumab, a subject’s ANC must be ≥1.5 × 109/L (≥1500/mm3) and platelet 
count must be ≥100 × 109/L (≥100,000/mm3).  Patritumab may be withheld for up to 
3 weeks to allow cell counts to recover to these values.  Dose administration may be 
delayed no more than 3 weeks to allow for recovery.  If the dose is delayed more than 3 
weeks, the subject will be withdrawn from study treatment, unless discussed and agreed 
with the sponsor.
All subjects should be carefully monitored for possible infusion reactions during the 
administration of patritumab/placebo. If, during infusion, a subject experiences mild to 
moderate symptoms suggestive of infusion reaction (such as fever and chills, with or 
without nausea/vomiting, pain, headache, dizziness, dyspnea, hypotension), slow down 
the infusion up
to 120 minutes (see Section
3.1.2.1
for administration of 
patritumab/placebo).  All subsequent infusions should be administered at the same slow 
rate (up to 120 minutes). 


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Interrupt patritumab/placebo infusion in all subjects experiencing severe infusion 
reactions (eg, dyspnea, clinically significant hypotension) and administer interventional 
medical therapy, which may include: epinephrine, corticosteroids, diphenhydramine, 
bronchodilators, and oxygen. Subjects should be evaluated and carefully monitored until 
complete resolution of signs and symptoms. 
Subjects experiencing severe infusion reactions will be permanently discontinued.
In the event of a dose reduction, the dose change(s) must be captured in the eCRF.  If 
questions or considerations regarding dose modification arise or a specific dose 
modification is needed, the medical monitor or designee should be consulted.  The 
contact information for the Daiichi Sankyo medical monitor is located in 
Section 15.2.1.1.
5.1.7.2.
Dose Modification of Cetuximab
Prior to first and all subsequent infusions of cetuximab, subjects must receive 
premedication with an antihistamine and a corticosteroid at least 1 hour prior to 
administration of cetuximab (please see package insert for further information).  Severe 
infusion-related reactions, including anaphylactic reactions, may commonly occur, in 
some cases with fatal outcome.  Occurrence of a severe infusion-related reaction requires 
immediate and permanent discontinuation of cetuximab therapy and may necessitate 
emergency treatment. Some of these reactions may be anaphylactic or anaphylactic in 
nature, accompanied by bronchospasms or urticaria, or represent a cytokine release 
syndrome.  Symptoms may occur during the first infusion and for up to several hours 
afterwards, or with subsequent infusions.  They can occur despite the use of 
premedication.  It is recommended to warn subjects of the possibility of such a late onset 
and instruct them to contact their physician if symptoms or signs of an infusion-related 
reaction occur.
If during the first infusion, infusion-related reaction occurs within the first 15 minutes, 
the infusion should be stopped.  If an infusion-related reaction develops later during the 
infusion or at a subsequent infusion, further management will depend on its severity:

Grade 1: continue slow infusion under close supervision

Grade 2: continue slow infusion and immediately administer treatment for 
symptoms

Grade 3 and 4: stop infusion immediately, treat symptoms vigorously, and 
contraindicate further use of cetuximab
Mild or moderate infusion-related reactions are very common, comprising symptoms 
such as fever, chills, dizziness, or dyspnea that occur in a close temporal relationship, 
mainly to the first cetuximab infusion.  If the subject experiences a mild or moderate 
infusion-related reaction, the infusion rate may be decreased.  It is recommended to 
maintain this lower infusion rate in all subsequent infusions.
Additionally, cetuximab must be immediately discontinued in case of:

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
Occurrence of a second infusion-related reaction, following administration of 
cetuximab at a slower infusion rate.

A fourth occurrence of Grade 3 skin reactions, despite appropriate dose 
reductions

Occurrence of Grade 4 skin reactions
A close monitoring of subjects, particularly during the first administration, is required.  
Special attention is recommended for subjects with reduced performance status and 
pre-existing cardiopulmonary disease.
When cetuximab is administered with platinum-based chemotherapy, the frequency of 
severe leukopenia or severe neutropenia may be increased and thus may lead to a higher 
rate of infectious complications such as febrile neutropenia, pneumonia, and sepsis 
compared to platinum-based chemotherapy alone.
If a subject develops an intercurrent illness (eg, infection) that, in the opinion of the 
Investigator and/or the Sponsor, mandates interruption of therapy, this intercurrent illness 
must resolve within a time frame such that no more than 2 consecutive cetuximab 
infusions are withheld.
When cetuximab is administered in combination with chemotherapeutic agents such as 
cisplatin or carboplatin, refer to their respective product information.  Chemotherapy 
must not be administered earlier than 1 hour after the end of the cetuximab infusion.
Cetuximab therapy will not be delayed for cisplatin-related toxicity.  Therefore, if the 
next infusion of cisplatin is delayed, the subject will continue to receive weekly infusions 
of cetuximab. In case of cetuximab-related toxicity, cisplatin will not be delayed and the 
planned schedule for administration should be maintained.  If the cetuximab therapy is 
terminated for cetuximab-related toxicity, cisplatin will be continued. If there is 
cetuximab-related toxicity that does not resolve to Grade 0 or 1 (or baseline grade if 
higher than Grade 1), cetuximab will be discontinued at the discretion of the investigator.
Dose modifications for cetuximab are described in Table 5.3 and Table 5.4.
Table 5.3:
Cetuximab Dose Modifications
Toxicity
Dose Reduction
Discontinuation
Infusion reaction Reduce infusion rate by 50% for 
CTCAE Grade 1 or 2 and non-serious 
CTCAE Grade 3 infusion reaction
Immediately interrupt and 
permanently discontinue cetuximab 
infusion for serious infusion 
reactions
CTCAE = Common Terminology Criteria for Adverse Events.


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Table 5.4:
Cetuximab Dose Modification Guidelines for Acneiform Rash
Severe 
Acneiform Rash
(Grade 3-4)
Cetuximab
Outcome
Cetuximab Dose 
Modification
1st occurrence
Delay infusion 1-2 weeks* Improvement
Continue at 250 mg/m2
No improvement
Discontinue cetuximab
2nd occurrence
Delay infusion 1-2 weeks* Improvement
Reduce dose to 200 mg/m2
No improvement
Discontinue cetuximab
3rd occurrence
Delay infusion 1-2 weeks* Improvement
Reduce dose to 150 mg/m2
No improvement
Discontinue cetuximab
4th occurrence
Discontinue
* If infusion is delayed >2 weeks, discontinue cetuximab treatment.
5.1.7.3.
Dose Modification of Cisplatin
Repeating administration of cisplatin must be delayed until normal values are achieved 
(wait one cycle for recovery) for the following parameters:

Serum creatinine < 1.5 mg/dL

Urea < 25 mg/dL

White blood cells > 4.0 x 109/L

Blood platelets > 100 x 109/L

Non-hematological cisplatin-related toxicities to resolve to ≤ Grade 1

However, skin reactions, paronychia, fatigue, ototoxicity, or neurotoxicity should 
resolve to ≤ Grade 2
Please see package insert for further information.
Nephrotoxicity
Cisplatin causes severe cumulative nephrotoxicity.  A urine output of 100 mL/hour or 
greater will tend to minimize cisplatin nephrotoxicity.  This can be accomplished by 
prehydration with 2 liters of an appropriate IV solution, and similar post cisplatin 
hydration (recommended 2,500 mL/m2/24 hours) or according to institutional standards.  
If vigorous hydration is insufficient to maintain adequate urinary output, an osmotic 
diuretic may be administered (eg, mannitol).
Neuropathies
Neuropathies may manifest by paresthesia, areflexia, and a proprioceptive loss of 
sensation of vibrations.  A neurologic examination must be carried out at regular 
intervals.
Ototoxicity


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Ototoxicity has been observed in up to 31% of patients treated with a single dose of 
cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high 
frequency range (4000 to 8000 Hz). 
Allergic phenomena
As with other platinum-based products, hypersensitivity reactions appearing in most 
cases during perfusion may occur, and necessitate discontinuation of the perfusion as an 
appropriate symptomatic treatment. 
Anaphylactic-like reactions to cisplatin have been observed.  These reactions can be 
controlled by administration of antihistamines, adrenaline, and/or glucocorticoids.
Hepatic function and hematological status
The hematological status and the hepatic function must be monitored at regular intervals.
Injection site reactions
Injection site reactions may occur during the administration of cisplatin.  Given the 
possibility of extravasation, it is recommended to closely monitor the infusion site for 
possible infiltration during drug administration.
Special care is required for subjects with acute bacterial or viral infections.
Table 5.5 lists toxicities and related dose modifications and discontinuations.
Table 5.5:
Cisplatin Dose Modifications and Discontinuations* for Toxicities
Toxicity
Dose Modification/Discontinuation
Hematological
A repeat course should not be given until circulating blood elements are at 
an acceptable level (ie, platelets ≥100 x 109/L, white blood cells ≥4 x 
109/L)  
Febrile 
neutropenia/infection
The first episode of febrile neutropenia or infection will result in 
reduction by 20% of cisplatin dose.
If there is a second episode, despite dose reduction, the subject must 
receive prophylactic antibiotics during subsequent cycles.
If there is a third episode, the subject will be withdrawn from study.
Neutropenia
Grade 2 or 3: cisplatin treatment delay until < Grade 1.
Grade 4: cisplatin treatment delay until < Grade 1; dose reduction of all 
further doses of cisplatin by 20%.
Nephrotoxicity
A repeat course of cisplatin should not be given until the serum creatinine 
is below 1.5 mg/100 mL, and/or the urea is below 25 mg/100 mL
Thrombocytopenia
Grade 1: cisplatin treatment delay until platelets ≥ 100,000/mm3.
≥ Grade 2: cisplatin treatment delay until platelets >100,000/mm3, dose
reduction of all further doses of cisplatin by 20%


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Toxicity
Dose Modification/Discontinuation
Organ Toxicity 
Grade 2: Delay chemotherapy until ≤ Grade 1. 
≥ Grade 3 or more: Delay chemotherapy until ≤ Grade 1; dose reduction 
of all further doses of cisplatin by 20%.
Do not delay or reduce cisplatin dose if there are asymptomatic increases 
in transaminases, cetuximab-induced skin reactions, and subclinical side 
effects (e.g. nausea, vomiting, alopecia, altered taste).
Ototoxicity
Criteria for hearing testing
Neuropathy
In case of sensory neuropathy ≥ Grade 2, change cisplatin to carboplatin
Note: Please refer to the cisplatin package insert for additional information on potential toxicities and their 
management. When cisplatin is administered in combination with other agents such as cetuximab, refer to their 
respective product information. *If events do not recover within 3 weeks, discontinue cisplatin treatment.
5.1.7.4.
Dose Modification of Carboplatin
Myelosuppression
Carboplatin myelosuppression is closely related to its renal clearance.  Subjects with 
abnormal kidney function or receiving concomitant therapy with other drugs with 
nephrotoxic potential are likely to experience severe and prolonged myelotoxicity.  Renal 
function parameters should therefore be carefully assessed.
Hematological toxicity
Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting.  
Anemia is frequent and cumulative.  Frequent monitoring of peripheral blood counts is 
recommended during and following therapy.  Carboplatin should not be repeated until 
after leukocytes, platelets, and neutrophils have returned to normal (Table 5.6). 
Hepatic and/or renal insufficiency
Renal or hepatic function impairment may be encountered with carboplatin.  Dose 
reduction or discontinuation of carboplatin is required in the presence of moderate to 
severe alterations in renal or hepatic function.
Allergic reactions
Infrequent allergic reactions such as erythematous rash, fever with no apparent cause, or 
pruritus, 
anaphylaxis, 
angioedema, 
and 
anaphylactoid 
reactions 
(including 
bronchospasm, urticarial, and facial oedema) may occur.  These occur more often during 
perfusion.  Discontinuation of the perfusion should be carried out immediately and 
appropriate symptomatic treatment must be given such as with antihistamines, 
adrenalines, and/or glucocorticoids.
Neurotoxicity 
Neurotoxicity such as paresthesia, decreased deep tendon reflexes, and ototoxicity are 
more likely in subjects older than 65 years old. Monitoring and neurological 
examinations should be carried out at regular intervals.


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Table 5.6:
Carboplatin Dose Modification for Toxicities
Toxicity
Dose Reductiona
Myelosuppression*
Platelets
Neutrophils
Adjusted Dose (from prior course)
> 100,000
> 1,500
No adjustment
50-100,000
500-1,500
No Adjustment
< 50,000
< 500
25% dose reduction
Nephrotoxicity*
Baseline creatinine clearance
Recommended Dose on Day 1
41-59 mL/min
AUC 3.75 (25% dose reduction)
30-40 mL/min
AUC 3.0 (40% dose reduction)
a
Initial dose is AUC 5 calculated by Calvert formula. AUC = area under the curve.
Note: Please refer to the carboplatin package insert for additional information on potential toxicities and 
their management.  When carboplatin is administered in combination with other agents such as 
cetuximab, refer to their respective product information.
*If events do not recover within 3 weeks, discontinue carboplatin treatment.
5.1.8.
Retention Samples
Not Applicable.
5.1.9.
Emergency Unblinding
In the case of a rare emergency where, in the opinion of the Investigator, discontinuation
of study drug is not sufficient and study treatment must be unblinded to evaluate a further 
course of medical treatment, the following procedures will apply:
The investigator is encouraged to contact the CRO medical monitor to discuss their 
rationale for unblinding. However, to prevent delays to the investigator or medical 
personnel responding to a potentially emergent situation, unblinding of the study 
treatment will not be dependent upon the investigator receiving approval from the CRO 
medical monitor (ie, the Investigator will be able to obtain the code break information 
independent of the CRO medical monitor).
The method for determining a subject's treatment assignment once a subject is 
randomized in the study is through the IxRS. The investigator and one designated sub-
investigator will have access to perform emergency unblinding in the IxRS. The 
treatment assignment of the selected subject randomized at their site will be revealed to 
the investigator performing the IxRS call upon completion of the emergency unblinding 
call.
The investigator must contact CRO medical monitor by telephone with an explanation of 
the need for opening the treatment assignment code within 24 hours of opening the code.
In the event of emergency unblinding, the subject will be informed about their treatment 
assignment.  Information about the treatment assignment must be restricted to designated 
study site staff/personnel who are providing immediate care to the subject.  Any 
documentation of the treatment assignment must be maintained separately (ie, a secured 


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file).  The information must not be included in the subject’s source files to ensure the 
treatment assignment will remain blinded to the CRO monitor and other study personnel 
who are not involved with the subject’s immediate care.
When an emergency unblinding has occurred, an automatic notification (via e-mail) will 
be sent to the investigator and selected Daiichi Sankyo study personnel from the IxRS 
vendor.  The notification will not contain any unblinding information.  This will trigger 
the follow up process to document the unblinding by completing the Emergency 
Unblinding by Investigator Form (to be provided to the CRO medical monitor by study 
personnel upon receipt of IxRS notification) and submission to Daiichi Sankyo Clinical 
Safety and Pharmacovigilance; please refer to the form for completion instructions.
Once the study treatment has been unblinded for a specific subject, the study treatment 
should be discontinued for the subject, and the subject should leave the study treatment 
phase.  The end of treatment and follow-up assessments for the subjects will be 
performed as defined in the protocol.
5.2.
Concomitant Medications
Subjects cannot receive any nonstudy anticancer therapy, hormonal therapy, or 
radiotherapy during the treatment period.
Use of hematopoietic growth factors, if required, are permitted in Cycle 1 In subsequent 
cycles, hematopoietic growth factors may be used for prophylaxis or treatment based on 
the clinical judgment of the Investigator.
Concomitant use of dietary supplements, medications not prescribed by the Investigator, 
and alternative/complementary treatments is discouraged, but not prohibited.
Please refer to package inserts for cetuximab, cisplatin, and carboplatin for additional 
information on use of concomitant medications.
All concomitant medication taken by subjects during the study must be recorded in the 
eCRF.
5.2.1.
Patritumab
Patritumab is contraindicated for subjects with known hypersensitivity to either the drug 
substance or inactive ingredients in the drug product.  There are no known 
contraindications. Drug-drug interaction studies have not yet been conducted.  
5.2.2.
Cetuximab
In combination with platinum-based chemotherapy, the frequency of severe leukopenia 
or severe neutropenia may be increased, and thus may lead to a higher rate of infectious 
complications such as febrile neutropenia, pneumonia, and sepsis compared to 
platinum-based chemotherapy alone. 


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5.2.3.
Cisplatin
Nephrotoxic substances
Concomitant administration of nephrotoxic (eg, cephalosporins, aminoglycosides, 
amphotericin B or contrast media) or ototoxic (eg, aminoglycosides) medicinal products 
will potentiate the toxic effect of cisplatin on the kidneys.  
Ototoxic substances
Concomitant administration of ototoxic (eg, aminoglycosides, loop diuretics) medicinal 
products will potentiate the toxic effect of cisplatin on auditory function.  Except for 
subjects receiving doses of cisplatin exceeding 60 mg/m2, whose urine secretion is 
< 1000 mL per 24 hours, no forced diuresis with loop diuretics should be applied in view 
of possible damage to the kidney tract and ototoxicity. 
Weakened live vaccines
Yellow fever vaccine is strictly contraindicated because of the risk of fatal systemic 
vaccinal disease.  In view of the risk of generalized illness, it is advisable to use an 
inactive vaccine if available. Live/attenuated or inactivated influenza vaccine is allowed. 
Antihistamines, Phenothiazines and others:
Simultaneous use of antihistamines, buclizine, cyclizine, loxapine, meclozone, 
phenothiazines, thioxanthenes or trimethobenzamines may mask ototoxicity symptoms 
(such as dizziness and tinnitus). 
Anticonvulsive substances
Serum concentrations of anticonvulsive medicines may remain at subtherapeutic levels 
during treatment with cisplatin. 
Anti-epileptics
In subjects receiving cisplatin and anticonvulsant agents, the serum level of the 
anticonvulsant agent might be reduced. This is probably due to reduced absorption and/or 
increased metabolism. In these subjects, the plasma levels of anticonvulsants should be 
monitored, and the dose adjusted accordingly. Prophylactic use of phenytoin or 
fosphenytoin is prohibited.
5.2.4.
Carboplatin
Concurrent therapy with nephrotoxic or ototoxic drugs such as aminoglycosides, 
vancomycin, capreomycin, and diuretics, may increase or exacerbate toxicity due to 
carboplatin induced changes in renal clearance.
Combination therapy with other myelosuppressive agents may require dose changes or 
rescheduling of doses in order to minimize the additive myelosuppressive effects.
Prophylactic use of phenytoin or fosphenytoin is prohibited.
Receiving yellow fever vaccine or live attenuated vaccines is prohibited.


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6.
STUDY PROCEDURES
A study visit schedule is provided in Table 17.2. Study treatments should be administered 
as specified in Section 3.1.2.
6.1.
Screening
6.1.1.
Tissue Screening
Samples must be taken from subjects who have recurrent or metastatic disease (rec/met). 
These samples must be from either rec/met archived or fresh biopsy material. Samples 
can derive from either primary recurrent tumor or from its lymph nodal metastases 
originating from the oral cavity, oropharynx, hypopharynx, and larynx. No additional 
treatment is allowed between biopsy and study entry. 
Tissue samples must be formalin fixed, paraffin embedded, slides cut of 5 microns, 
unstained and unbaked. Please refer to the laboratory manual for additional information 
on management of tissue samples. 
The following procedures will be conducted:

Obtain written consent from the subject to collect tissue or perform a biopsy 

If a tumor biopsy is performed, record only SAEs directly related to the 
procedure.

Samples will be analyzed for and must meet eligibility criteria:

HRG expression   

HPV status or p16 is required. These results may be obtained from either a 
local lab or samples sent to the central lab
6.1.2.
Screening (Up to 14 Days Before the First Dose of Study Treatment 
Unless Otherwise Noted)
Screening procedures can be done at the same time as tissue screening (Section 6.1.1) at 
the discretion of the Investigator.  
The following activities and/or assessments will be performed at/during screening (within 
14 days before the first dose of study treatment [unless otherwise noted]):

Obtain signed informed consent 

Obtain signed informed consent for pharmacogenomics (optional)

Evaluation of inclusion and exclusion criteria

Confirm results of the HRG expression level and HPV or p16 status.    

Record demographic and medical history information

Including smoking history


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
Record AEs and concomitant medications

Perform a physical examination, including vital sign measurements, blood 
pressure, heart rate, temperature, weight, and height. Height will be measured
only at Screening

Assess functional status using the ECOG Performance Status Scale 
(Section 10.1)

Perform an echocardiogram or multigated acquisition (MUGA) scan (the 
same test must be used for a subject throughout the study) (Section 9.11.1)

Perform a 12-lead ECG

Collect blood sample for complete blood count (CBC) (Section 9.7)

Collect blood sample for coagulation-only at Screening (Section 9.7)

Collect blood sample for serum chemistry (Section 9.7)

Obtain urine sample for urinalysis (Section 9.7)

Perform a serum or urine pregnancy test for female subjects of childbearing 
potential (must be confirmed negative before dosing). Additional pregnancy 
testing may be done at the discretion of the Investigator and/or if required by 
local regulations for women of child-bearing potential (Section 9.7)

Perform radiographic tumor assessments after eligibility is determined.
Existing radiographic scans can be used for the baseline evaluation if the 
scans were performed within 4 weeks prior to randomization. Computed 
tomography (CT) and/or magnetic resonance imaging (MRI) (spiral CT or 
MRI with ≤ 5 mm cuts) should be used for tumor assessment unless another 
modality of radiographic disease assessment is necessary for the lesions per 
RECIST guidelines Version 1.1, (see Appendix 17.3)
6.1.3.
Randomization 
For subjects who are eligible to participate in the study, complete the following:

Randomize subject in the IxRS

Study treatment should begin within 3 business days after randomization
6.2.
Treatment Period
A hospital overnight stay associated with study procedures or treatment is allowed and 
will not be reported as an SAE (see Section 9.4.2).
Additional pregnancy testing may be done during the treatment period at the discretion of 
the Investigator and/or if required by local regulations for women of child-bearing 
potential.


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6.2.1.
Cycle 1: Week 1, Day 1
Pre-dose

Perform a physical examination

Weight measured within 3 days prior to Day 1 may be used to calculate 
the drug dose

Vital sign measurements (blood pressure, heart rate, temperature)

Assess functional status using the ECOG Performance Status Scale 
(Section 10.1).

Record AEs

Record concomitant medications

Have subject complete the PRO assessments before any study-related 
procedures are performed

Collect blood sample for CBC (Section 9.7)-within 3 days prior to visit

Collect blood sample for serum chemistry (Section 9.7)-within 3 days prior to 
visit

Collect blood sample for HAHA-within 3 days prior to visit (Section 8.4 and
Table 8.1)

Collect blood sample for sparse PK (Table 8.1)

Collect blood sample for pharmacogenetics (PGx) (optional)

Collect blood samples for additional biomarkers
Study Treatment
Information for dosing and administration is found in Section 3.1.2 .  Study drugs should 
be administered consecutively in the order below:

Administer patritumab IV as specified in Section 3.1.2

Administer cetuximab IV as specified in Section 3.1.2

Administer cisplatin (or carboplatin) IV one hour after cetuximab, as specified 
in Section 3.1.2.
End of Patritumab, Cetuximab, and Cisplatin or Carboplatin Infusions

Perform vital sign measurement

Record concomitant medications and AEs throughout administration of study 
drugs

Sparse PK: collect a blood sample for PK at end of patritumab infusion (EOI)
at 1 hr ± 10 min for all subjects (Table 8.1)

Intense PK substudy


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
Collect blood sample for PK at 3 hrs ±10 min after start of patritumab 
infusion (approximately EOI for cetuximab) (Table 8.2)

Collect blood sample for PK at 4 hrs ±10 min after start of patritumab 
infusion (or 4.25 hrs ± 10 min, approximately EOI for carboplatin for 
those subjects receiving carboplatin) (Table 8.2)

Collect blood sample for PK at 5 hrs ± 10 min after start of patritumab 
infusion) (approximately EOI for cisplatin for those subjects receiving 
cisplatin) (Table 8.2)

Collect blood sample for PK at 6 hrs ± 10 min after start of patritumab
infusion (Table 8.2)

Collect blood sample for PK at 7 hrs ± 10 min after start of patritumab
infusion (Table 8.2)
6.2.2.
Cycle 1: Week 1, Day 2

Intense PK substudy: collect blood sample for PK at 24 hrs ± 1hr after start of 
patritumab infusion (Table 8.2)
6.2.3.
Cycle 1: Week 1, Day 3

Intense PK substudy: collect blood sample for PK at 48 hrs ± 1hr after start of 
patritumab infusion (Table 8.2)
6.2.4.
Cycle 1: Week 2, Day 8

Physical examination

Vital signs

ECOG Performance Status

Record concomitant medications and AEs

Blood samples for CBC (hematology with differential and platelet count), 
(Section 9.7)-may be collected within 3 days prior to visit

Serum chemistries-may be collected within 3 days prior to the visit

Intense PK substudy: collect blood sample for PK at 168 hrs ± 24 hrs
(Table 8.2)-within 3 days prior to visit

Administer cetuximab IV (infused weekly) as specified in Section 3.1.2 (given 
on Day 8 and Day 15 of all cycles)
6.2.5.
Cycle 1: Week 3, Day 15

Physical examination

Vital signs

ECOG Performance Status


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
Record concomitant medications and AEs

Blood samples for CBC (hematology with differential and platelet count) 
(Section 9.7)-may be collected within 3 days prior to visit

Serum chemistries-may be collected within 3 days prior to visit

Intense PK substudy: collect blood sample for PK at 336 hrs ± 1 day
(Table 8.2)

Administer cetuximab IV (infused weekly) as specified in Section 3.1.2 (given 
on Day 8 and Day 15 of all cycles)
6.2.6.
Cycle 2 and 3
6.2.6.1.
Cycle 2, Day 1

Collect blood samples for additional biomarkers
6.2.6.2.
Cycles 2 and 3, Day 1
Before Start of Patritumab Infusion

Physical examination *

Vital signs*

Weight*

ECOG Performance Status 

At Cycle 3 only, perform an echocardiogram or MUGA scan (the same test 
must be used for a subject throughout the study)

Record concomitant medications and AEs*

Have subject complete the PRO assessments before any study-related 
procedures are performed

Collect blood sample for CBC with differential and platelet count*

Collect blood sample for serum chemistries*

For Cycle 2 Sparse PK: collect blood sample for HAHA/patritumab PK 
(Table 8.1). 

For subjects participating in the Intense PK substudy, the preinfusion 
patritumab PK sample is also the PK at 504 hrs ± 1 day (Table 8.2)

At Cycle 3 Sparse PK: collect blood sample for PK at preinfusion and the 
patritumab EOI at 1 hr ±10 min for all subjects (Table 8.2)

Serum sample for HAHA
Note: * Can be collected on Days 8 and 15 at the discretion of the Investigator.


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Study Treatment Administration

Administer patritumab IV (infused once every 3 weeks) as specified in
Section 3.1.2

Administer cetuximab IV (infused weekly) as specified in Section 3.1.2
Administer cisplatin or carboplatin IV (infused every 3 weeks, for a maximum 
of 6 cycles) as specified in Section 3.1.2
6.2.7.
Cycle 4 and all Subsequent Cycles, Day 1
6.2.7.1.
Day 1

Physical examination*

Vital signs*

Weight*

ECOG Performance Status (Section 10.1)

At visits for every third subsequent cycle (eg, Cycles 6, 9, 12 …) conduct an 
echocardiogram or MUGA scan (the same test must be used for a subject 
throughout the study)

Record concomitant medications and AEs*

Have subject complete the PRO assessments before any study-related 
procedures are performed

Collect blood sample preinfusion for CBC with differential and platelet count*

Collect blood sample preinfusion for serum chemistries*
Note: * Can be collected on Days 8 and 15 in Cycle 4 and all subsequent cycles at the 
discretion of the Investigator.
Study Treatment Administration

Administer patritumab IV (infused once every 3 weeks) as specified in 
Section 3.1.2

Administer cetuximab IV (infused weekly) as specified in Section 3.1.2

Administer cisplatin or carboplatin IV (infused every 3 weeks, for a maximum 
of 6 cycles) as specified in Section 3.1.2
End of Cycle 6 and Every 4 Cycles

Collect blood samples for additional biomarkers
6.2.8.
Every 6 Weeks

Frequency of tumor assessments will be every 6 weeks to Week 24 (±3 days); 
every 12 Weeks (±7 days) thereafter


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6.2.9.
End of Study Treatment Visit (21 days after last dose)
At the end of study treatment, the following procedures will be performed. 

Physical examination

Vital signs 

Weight

ECOG Performance Status (Section 10.1)

Perform an echocardiogram or MUGA scan

Perform a 12-lead ECG

Record concomitant medications and AEs

Have subject complete the PRO assessments before any study-related 
procedures are performed

Collect blood sample for CBC with differential and platelet count

Collect blood sample for serum chemistries

Collect urine sample for urinalysis (Section 9.7)

Sparse PK: collect a blood sample for PK (Table 8.1)

Collect blood sample for HAHA

Perform a serum or urine pregnancy test for female subjects of childbearing 
potential

Tumor measurement assessments unless it was performed within the previous 
6 weeks or the previous assessment demonstrated disease progression

Collect blood samples for additional biomarkers
If there is a significant clinical or laboratory abnormality in need of monitoring beyond 
the end-of-study treatment visit, subjects will be followed until resolution of the 
abnormality, until it is considered stable, or the subject begins another cancer treatment. 
For subjects with positive HAHA at the end-of-study treatment visit, additional serum 
samples for HAHA and PK should be collected every 3 months until HAHA titers return 
to baseline or until the start of another cancer therapy. Samples will be collected up to 1 
year from the last dose of study drug or collected up to the time that a subject starts 
another cancer therapy, whichever occurs first.
6.2.10.
40 Days After Last Dose
At 40 days after the last dose of any study drug administered, a telephone call will be 
placed to the subject to record AEs (See Section 4.1.5).

Collect blood samples for additional biomarkers


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6.2.11.
Discontinuation From Study Treatment
Subjects discontinued from study treatment without documented (by imaging) PD, 
withdrawal of consent, death or loss to follow-up should continue tumor evaluation at 
6-week intervals up to the first 24 weeks after randomization, then every 12 weeks 
(±7 days) until disease progression, start of new anticancer therapy, death, withdrawal of 
consent, loss to follow-up, or study closure. 
6.2.12.
Subjects Deriving Clinical Benefit
Subjects receiving clinical benefit (SD or better) from study treatment at the time of 
closure of the main study may be offered the opportunity to continue study treatment in 
an open label extension phase (see Section 6.5).
6.3.
Follow-up Survival
After discontinuation from study treatment, follow-up information for survival will be 
obtained per telephone approximately every 3 months for a minimum of 13 months.
6.4.
Protocol Deviations
The investigator should conduct the study in compliance with the protocol agreed to by 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRB/IEC.
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject.  
Sponsor must be notified of all intended or unintended deviations to the protocol (eg, 
inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis.
The investigator, or person designated by the investigator, should document and explain 
any deviation from the approved protocol.
If a subject was ineligible or received the incorrect dose of investigational treatment, and 
had at least one administration of investigational product, data should be collected for 
safety purposes.
The Investigator should notify the IEC or IRB of deviations from the protocol in 
accordance with local procedures.
6.5.
Extension Phase
Subjects receiving clinical benefit (SD or better) from study treatment at the time of 
closure of the main study may be offered the opportunity to continue study treatment. 
After database lock individual sites will be informed of subject treatment. Subjects will 
be provided open-label treatment in an extension phase of this study.
For subjects continuing in the extension phase, the following study procedures will be
performed: physical examination, weight, vital signs, hematology, blood chemistry, 
HAHA levels (and PK) if HAHA is positive at the end of study treatment, blood samples
for biomarkers, and AEs (see Extension Phase Schedule of Events, Table 17.3).


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7.
EFFICACY ASSESSMENTS
Tumor response assessments, including subjects who discontinued from treatment, will 
be performed every 6 weeks (± 3 days) for the first 24 weeks independent of treatment 
cycle until disease progression, death, start of new anticancer therapy, withdrawal of 
subject consent, lost to follow-up, or study closure, whichever occurs first. After 24 
weeks, tumor assessments will be performed every 12 weeks (± 7 days).
7.1.
Primary Efficacy Variable
The primary efficacy variable is PFS.  This is defined as the time from the date of 
randomization to the earlier of the dates of the first objective documentation of 
radiographic disease progression (per RECIST v1.1 as assessed by investigator-see 
Appendix 17.3) or death due to any cause. Progressive Disease is defined as ≥20% 
increase in the sum of diameters of target lesions; taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm.  (Note: the appearance of one or more new lesions is also considered progression). 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“clinical progression.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of 
an objective response: it is a reason for stopping study therapy.  The objective response 
status of such subjects is to be determined by evaluation of target and non-target disease.  
If a radiographic tumor assessment has not been performed within 4 weeks of the time of 
clinical progression, then another radiographic assessment should be performed without 
waiting for the next regularly scheduled scan.
For equivocal findings of progression (ie, very small and uncertain new lesions, cystic 
changes, or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
7.2.
Secondary Efficacy Variable(s)

Overall survival and objective response rate 
7.3.
Exploratory Efficacy Variable(s)

Duration of response, time to response, time to disease progression, duration 
of SD


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8.
PHARMACOKINETIC/PHARMACODYNAMIC 
ASSESSMENTS
8.1.
Pharmacokinetic (PK) Variable(s)
All subjects will have a PK sample for serum patritumab collected at Cycles 1- 3 and at 
End of Study Treatment Visit as shown in Table 8.1. This will be a sparse PK assessment 
(limited sampling).
Table 8.1:
Sparse PK Assessments (Patritumab Only) for All Subjects 
Cycle 1
Cycle 2
Cycle 3
End of Treatment
Pre-inf (collected 
with HAHA 
sample)
EOI
Pre-inf (collected 
with HAHA 
sample)
Pre-inf (collected 
with HAHA 
sample)
EOI
Collected with 
HAHA sample
Pre-inf = Preinfusion, EOI = end of infusion, HAHA = human antihuman antibody. EOI samples should be 
collected ± 10 min of the end of patritumab infusion.
For a subset of 30 subjects, a blood sample for PK analyses of patritumab, cetuximab, 
and platinum concentrations will be obtained at the time points, relative to the start of 
patritumab infusion at Cycle 1, shown in Table 8.2. This will be an intense PK 
assessment.
Table 8.2:
Sub Study: Intensive PK Assessments Relative to the Start of 
Patritumab Infusion at Cycle 1 [n = 30]
Study 
Treatment
Pre-
inf
Day 1
Day 
2
24 h
± 1 h
Day 
3
48 h
± 1 h
Day 8 
168 h  
± 24 h
Day 15
336 h
± 24 h
Day 21
504 h
± 24 h
1 h
(EOI)
±10 
min
3 h
±10
min
4 h
±10
min
5 h
±10
min
6 h
±10
min
7 h
±10 
min
Patritumab
X
X
X
X
X
X
X
X
X
X
X
X
Cetuximab
X
EOI
X
X
X
X
X
X
X
Cisplatin
X
EOI
X
X
X
X
or
Carboplatin
X
4.5 h
EOI
X
X
X
X
X
Pre-inf = Preinfusion, EOI = End of infusion, h = hours, min = minutes.
Note: One blood sample to produce 3 mL of serum sample will be collected at each time point. The 
resulting serum will be divided into 3 aliquots of 1 mL for analysis of each analyte depending on the dose 
regimen. Further details will be provided in the lab manual.
Patritumab will be infused over 1 hour followed by cetuximab infused over 2 hours (end 
of infusion at ~3 h) and then a 1 h pause (~4 h). Then cisplatin will be infused over 
1 hour (end of infusion ~5 h) or carboplatin infused over 30-60 minutes (end of infusion 
~4.5 h). Subjects will remain in the clinic for hydration following cisplatin/carboplatin 


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infusions for approximately 2 hours following infusions to complete hydration (ie, ~7 h
in total). Only one blood sample will be collected at each scheduled time point and the 
resulting serum will be aliquoted for each analyte. Blood collection should approximately 
correspond to EOI of each drug as listed, at the nominal times defined relative to the start 
of patritumab infusion.
Serum concentrations of patritumab, cetuximab, and platinum will be measured, as 
appropriate, using validated assays. Specific instructions for collection and shipping of 
PK samples will be provided in the Laboratory Manual.
8.2.
Pharmacodynamic Variable(s)
Not applicable.
8.3.
Predictive Biomarker and Exploratory Variable(s)
A predictive biomarker will be analyzed with the intent of identifying those subjects who 
might derive clinical benefit from treatment with patritumab.  Heregulin is the candidate 
biomarker prospectively selected as the single predictive biomarker. Heregulin messenger 
RNA will be measured in tumor samples using a quantitative reverse transcription 
polymerase chain reaction assay.
Subjects with HPV positive status will be included. Molecular and epidemiological 
studies strongly suggest HPV-positive oropharyngeal cancers comprise a distinct 
molecular, clinical, and pathologic disease entity that is likely associated with HPV 
infection and for which SCCHN patients who are HPV positive have a markedly 
improved prognosis. In addition, it has been shown that other SCCHN subtypes have 
been found to be p16 positive such as nasopharyngeal, hypopharyngeal, laryngeal, and in 
the oral cavity.5 Therefore, HPV status or p16 will be evaluated in all tumor tissue in this 
study.
Further exploratory tissue, soluble, or genomic biomarkers in subject tissue and blood 
samples (possibly including circulating cell-free DNA and exosomes) may be analyzed 
based on emerging scientific knowledge to better understand the target disease and also 
the effects of study treatment.
For instructions on management of blood and tissue samples please refer to the laboratory 
manual.
8.4.
Human Antihuman Antibodies 
The formation of antibodies to patritumab will be characterized by a screening test for 
HAHA and, if positive, a confirmatory test to determine antibody titers.  If antibody titers 
indicate HAHA to patritumab are present, then the sample will be assayed to determine 
whether antibodies are neutralizing.
Blood samples will be collected within 3 days prior to Day 1 of Cycle 1 (baseline), Cycle 
2 (preinfusion), Cycle 3 (preinfusion), and at End of Study Treatment visit.  For subjects 
with positive HAHA at the End of Study Treatment visit, additional serum HAHA and 
PK samples should be collected every 3 months up to 1 year from the last dose of study 


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drug or if the subject starts another therapy for cancer, or withdraws consent from the 
study, whichever occurs first. Detection of HAHA formation in serum samples will be 
performed using validated assays.
For instructions on management of HAHA samples please refer to the laboratory manual.
8.5.
Pharmacogenomics
Blood samples will be collected for pharmacogenetic sample banking from subjects who 
have provided a separate informed consent for this part of the study as an exploratory 
objective (Section 2.1.3).  Participation in this part of the study is optional for all 
subjects.  For those subjects who choose to participate, samples will be banked for 
possible future pharmacogenetic and germ-line DNA analysis.  These samples may be 
analyzed only for genes suspected to contribute to the safety and efficacy of the study 
medications.  
Samples will be retained until the DNA has been exhausted or until the Sponsor instructs 
the genotyping contractor to destroy the sample (in accordance with laboratory 
procedures).  During the period of storage, the DNA sample will not be immortalized or 
sold to anyone.  Subjects will have the right to withdraw consent and have their sample 
destroyed at any time.
For instructions on management of pharmacogenomics, please refer to the laboratory 
manual.


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9.
SAFETY ASSESSMENTS
9.1.
Adverse Events
All clinical AEs occurring after the subject signs the Informed Consent Form for general 
study participation and up to 40 days after the last dose of any study drug administered, 
whether observed by the investigator or reported by the subject, will be recorded on the 
Adverse Event CRF page.  Medical conditions (including laboratory values/vital signs 
that are out of range) that were diagnosed or known to exist prior to Informed Consent
will be recorded as part of medical history.  
All AEs, SAEs, and events of special interest are to be reported according to the 
procedures in Section 9.5.
Any laboratory findings should be appraised by the investigator as to clinical 
significance.  An isolated abnormal laboratory result (ie, not related to a reported 
diagnosis) should be reported as an AE if it is symptomatic, leads to study drug reduction 
or discontinuation, requires corrective treatment, or is defined as an AE of Special 
Interest in Section 9.3.
At each visit, the investigator will determine whether any AEs have occurred by 
evaluating the subject.  Adverse events may be directly observed, reported spontaneously 
by the subject or by questioning the subject at each study visit.  Subjects should be 
questioned in a general way, without asking about the occurrence of any specific 
symptoms. The Investigator must assess all AEs to determine seriousness, severity, and 
causality, in accordance with the definitions in Section 9.4. The Investigator’s assessment 
must be clearly documented in the site’s source documentation with the Investigator’s 
signature.
Always report the diagnosis as an AE or SAE term.  When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available.  If the signs and 
symptoms are distinct and do not suggest a common diagnosis, report them as individual
entries of AE or SAE.  For events that are serious due to hospitalization, the reason for 
hospitalization must be reported as the SAE (diagnosis or symptom requiring 
hospitalization).  A procedure is not an AE or SAE, but the reason for the procedure may 
be an AE or SAE.  Pre-planned (prior to signing the Informed Consent Form) procedure 
or treatment requiring hospitalization for pre-existing conditions which do not worsen in 
severity should not be reported as SAEs (see Section 9.4 for Definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE. Disease progression is a study endpoint and consequently, should not be reported 
as an AE/SAE.  However, when a subject dies from disease progression with no other 
immediate causes, “disease progression” should be reported as an SAE on the Serious 
Adverse Event Report (SAVER) form (see Section 9.5) and recorded on the patient 
outcome eCRF. In addition, any serious, untoward event that may occur subsequent to the 
reporting period that the Investigator assesses as related to study drug should also be 
reported and managed as an SAE.


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The Investigator should follow subjects with AEs until the event has resolved or the 
condition has stabilized.  In case of unresolved AEs, including significant abnormal 
laboratory values at the end of study assessment, these events will be followed until 
resolution or until they become clinically not relevant.
9.2.
Safety Endpoints
Not applicable
9.3.
Events of Special Interest
9.3.1.
Combined Elevations of Aminotransferases and Bilirubin
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the criteria of a potential Hy’s Law case (ALT or 
AST ≥ 3 x ULN with simultaneous total bilirubin level > 2 x ULN) should always be 
reported to the Sponsor using a SAVER form with the investigator’s assessment of 
seriousness, causality, and a detailed narrative.16 In addition, an eCRF for liver toxicity 
should be completed (See Section 9.5).
If the subject discontinues study drug due to liver enzyme abnormalities, the subject will 
be followed until the abnormality resolves or is considered stable.
9.3.2.
Interstitial Lung Disease
In a subject who develops an acute onset of new or progressive pulmonary symptoms, 
such as dyspnea, cough or fever, study treatment should be interrupted pending 
diagnostic evaluation. If interstitial lung disease (ILD) is diagnosed by the Investigator, 
the subject should be treated immediately and permanently discontinued from study 
treatment.  Information relevant to safety reporting of ILD will be captured on the eCRF.
9.4.
Definitions
9.4.1.
Adverse Event 
An AE is any untoward medical occurrence in a patient, or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An AE can, therefore, be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.17
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine those circumstances or abnormal laboratory findings which should be 
considered AEs.
9.4.2.
Serious Adverse Event 
Any untoward medical occurrence that at any dose:

Results in death


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
Is life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect, or

Is an important medical event
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.17
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias, or development of drug dependency or drug abuse.
Note:

A procedure is not an AE or SAE, but the reason for the procedure may be an 
AE or SAE

Pre-planned (prior to signing the Informed Consent Form) procedures or 
treatment requiring hospitalizations for pre-existing conditions which do not 
worsen in severity are not SAEs
9.4.3.
AE Severity
The following definitions should be used to assess intensity of AEs according to the latest 
NCI CTCAE:

Grade 1 Mild: Awareness of sign or symptom, but easily tolerated, ie, does 
not interfere with subject’s usual function

Grade 2 Moderate: Discomfort enough to cause interference with usual 
activity

Grade 3 Severe: Incapacitating with inability to work or do usual activity, ie, 
interferes significantly with subject’s usual functions

Grade 4: Life-threatening consequences; urgent intervention indicated

Grade 5: Death related to AE
The NCI CTCAE guidelines do not allow certain grades for certain AEs.  For example, 
pain can be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can 
only be Grade 4 or 5 (ie, can only be life-threatening or fatal).  In addition, alopecia can 
only be Grade 1 or 2.  The NCI CTCAE guidelines should be followed closely.
Severity vs. Seriousness: Severity is used to describe the intensity of a specific event, 
while the event itself, however, may be of relatively minor medical significance (such as 


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severe headache).  This is not the same as "seriousness," which is based on patient/event 
outcome at the time of the event. For example, the NCI CTCAE Grade 4 (life-threatening 
consequences; urgent intervention indicated, or disabling) is assessed based on unique 
clinical descriptions of severity for each AE, and these criteria may be different from 
those used for the assessment of AE seriousness.  An AE assessed as Grade 4 based on 
the NCI CTCAE grades may or may not be assessed as serious based on the seriousness 
criteria.
9.4.4.
Causality Assessment
The investigator should assess causal relationship between an AE and each of the study 
drugs on the basis or his/her clinical judgment and the following definitions.  The 
causality assessment should be made based on the available information and can be 
updated as new information becomes available.

1 = Related:

The AE follows a reasonable temporal sequence from study drug 
administration, and cannot be reasonably explained by the subject’s 
clinical state or other factors (eg, disease under study, concurrent diseases, 
and concomitant medications)

The AE follows a reasonable temporal sequence from study drug 
administration, and is a known reaction to the drug under study or its 
chemical group, or is predicted by known pharmacology

2 = Not Related:

The AE does not follow a reasonable sequence from study product 
administration, or can be reasonably explained by the subject’s clinical 
state or other factors (eg, disease under study, concurrent diseases, and 
concomitant medications)
9.4.5.
Action Taken Regarding the Study Product

1 = Dose Not Changed: No change in study drug dosage was made

2 = Drug Withdrawn: The study product was permanently stopped

3 = Dose Reduced: The dosage of study product was reduced

4 = Drug Interrupted: The study product was temporarily stopped
9.4.6.
Adverse Event Outcome

1 = Recovered/Resolved

The subject fully recovered from the AE with no residual effect observed

2 = Recovered/Resolved with Sequelae

The residual effects of the AE are still present and observable

Include sequelae/residual effects


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
3 = Not Recovered/Not Resolved

The AE itself is still present and observable

4 = Fatal

5 = Unknown
9.4.7.
Other Action Taken for Event

1 = None

No treatment was required

2 = Medication required

Prescription and/or over-the-counter medication was required to treat the 
AE

3 = Other
9.5.
Safety Reporting – Procedure for Investigators 
All AEs, SAEs, and events of special interest will be reported in the eCRF.  In addition, 
the Investigator should report the following types of events on a SAVER form within 24 
hours of becoming aware of them:

SAEs (see Section 9.4.2)

Hepatic events, both serious and nonserious, presenting with combination 
abnormalities meeting criteria for a potential “Hy’s law” case (ie, ALT or 
AST ≥ 3 x ULN, with simultaneous total bilirubin > 2 x ULN; see 
Section 9.3.1)
All events (serious and nonserious) must be reported with the Investigator’s assessment 
of the event’s seriousness, severity, and causal relationship to study drug.  A detailed 
narrative summarizing the course of the event, including its evaluation, treatment, and 
outcome should be provided. Specific or estimated dates of event onset, treatment, and 
resolution should be included when available.  Medical history, concomitant medications, 
and laboratory data that are relevant to the event should also be summarized in the 
narrative.  For fatal events, the narrative should state whether an autopsy was or will be 
performed, and should include the results if available. Source documents will be retained 
in site’s files and should not be submitted to the Sponsor for SAE reporting purposes.
Urgent safety queries must be followed up and addressed promptly. Follow-up 
information and response to non-urgent safety queries should be combined for reporting 
to provide the most complete data possible within each follow-up.
Please call the local SAE Hotline number (Section 15.2.1.5) or your study monitor for 
any questions on SAE reporting.


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9.5.1.
Notifying Regulatory Authorities, Investigators, and IRBs/IECs
Daiichi Sankyo and/or CRO will inform Investigators, IRBs/IECs, and regulatory 
authorities of any Suspected Unexpected Serious Adverse Event Reactions occurring in 
other study centers or other Daiichi Sankyo studies of the investigational product, as 
appropriate per local reporting requirements.
9.6.
Exposure In Utero During Clinical Studies
Daiichi Sankyo must be notified of any subject who becomes pregnant while receiving or 
within 40 days of discontinuing the investigational product. Although pregnancy is not 
technically an AE, all pregnancies must be followed to conclusion to determine their 
outcome.  This information is important for both drug safety and public health concerns.  
It is the responsibility of the Investigator, or designee, to report any pregnancy in a 
female subject using the Exposure In Utero Reporting form.  Please contact your study 
monitor to receive the Exposure In Utero Reporting Form upon learning of a pregnancy.  
The Investigator should make every effort to follow the subject until completion of the 
pregnancy.  If the outcome of the pregnancy meets the criteria for immediate 
classification as a SAE (ie, post-partum complications, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly, including that in an aborted fetus), the 
Investigator should follow the procedures for reporting SAEs outlined in Section 9.5.
9.7.
Clinical Laboratory Evaluations
Safety laboratory assessments will include hematology, serum chemistry, coagulation,
and urinalysis.

Coagulation (only at Screening): prothrombin time, international normalized 
ratio, and partial thromboplastin time

Hematology: CBC including hemoglobin, hematocrit, white blood cell count 
with 5 part differential (including ANC), red blood cell, and platelet count

Serum chemistry: bicarbonate, calcium, phosphorus, magnesium, albumin, 
glucose, serum creatinine, uric acid, total protein, urea, AST, ALT, lactic 
dehydrogenase, alkaline phosphatase, total and direct bilirubin, sodium, 
potassium, and chloride

Routine urinalysis: dipstick and microscopy (if indicated), including protein, 
specific gravity, glucose, and blood

Serum or urine β-HCG pregnancy test
At Screening, either GFR or the estimated serum creatinine clearance (mL/min) as an 
estimate of GFR will be calculated. The estimated serum creatinine clearance rate (CrCl; 
mL/min) will be calculated using the modified Cockcroft-Gault equation (Appendix 
17.1). The estimated GFR will also be calculated before each cisplatin or carboplatin 
administration. This will be performed only until completion of chemotherapy.
All laboratory values must be assessed by the Investigator as to clinical significance.  All 
abnormal laboratory values considered clinically significant by the investigator or NCI 


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CTCAE Grade ≥3 should be recorded on the AE page of the eCRF. If the abnormal 
laboratory value constitutes an SAE, a SAVER form should be submitted and other 
relevant procedures must be followed (see Section 9.4.2).  Abnormal laboratory values 
(NCI CTCAE Grade 3 or 4) occurring during the clinical study will be followed until 
repeat test results return to normal (or baseline), stabilize, or are no longer clinically 
significant.
9.8.
Vital Signs
Vital sign measurements include blood pressure, heart rate, temperature, height, and 
weight.
9.9.
Electrocardiograms
A 12-lead ECG will be performed within 14 days prior to Screening, at the End-of-Study
Treatment visit, and during the study at the discretion of the Investigator.
9.10.
Physical Findings
Physical examinations will evaluate the following body systems/organs:  respiratory, 
cardiovascular, gastrointestinal, musculoskeletal, genitourinary/reproductive (optional), 
psychiatric (optional), hematological, neurological, immunological, head, eyes, ears, nose 
and throat, and other. Abnormal physical examination findings that are new or changed 
will be reported as AEs; otherwise, physical examination observations will not be 
recorded.
9.11.
Other Safety Assessments
9.11.1.
Echocardiograms or MUGA (LVEF Assessment)
To monitor for possible effects of treatment on cardiac function, LVEF will be assessed 
at Screening, Cycle 3, and then every third subsequent cycle, the End of Treatment Visit, 
and as otherwise clinically indicated using either echocardiography or MUGA scanning 
(if MUGA is considered local standard of care). The same test must be used for a subject 
throughout the study. Clinically significant changes from baseline in LVEF will be 
reported as AEs.
9.11.2.
Human Antihuman Antibodies
The presence of anti patritumab neutralizing antibody in serum will be assessed. Blood 
samples will be taken on Day 1 of Cycle 1 (preinfusion), Cycle 2 (preinfusion), Cycle 3 
(preinfusion), and at End-of-Study Treatment visit. A PK sample will be collected at the 
same time of HAHA collection for interpretation of HAHA results, which will be 
provided to the study sites. For subjects with positive anti patritumab neutralizing 
antibody on the serum sample drawn at the end of study treatment visit, additional serum 
samples should be obtained for antibodies, until the antibody level returns to baseline (or 
becomes negative) or up to 1 year from the last dose of study drug or if the subject starts 
another therapy for cancer, whichever occurs first. 


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10.
OTHER ASSESSMENTS
10.1.
Eastern Cooperative Oncology Group Performance Status
The ECOG performance status will be determined at Screening, and then at each 
scheduled visit throughout the study. See Table 10.1 below.
Table 10.1:
Eastern Cooperative Oncology Group Performance Status Scale 
Grade Description18
0
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction.
1
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work).
2
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours.
3
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair.
5
Dead.
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-55.
10.2.
Patient-Reported Outcomes
Patient-reported outcomes will be used to evaluate study treatment in subjects treated 
with patritumab + cetuximab + platinum-based therapy compared to 
placebo + cetuximab + platinum-based therapy (see Appendix 17.2).  
10.2.1.
Functional Assessment of Cancer Therapy—Head and Neck (FACT-
H&N) Instrument
The FACT-H&N is a multidimensional, self-report quality of life instrument specifically 
designed for use with head and neck cancer patients.19,20,21 It consists of 28 core items, 
the FACT-G, which assess patient function in four domains: Physical, Social/Family, 
Emotional, Functional well-being, and relationship with doctor which is further 
supplemented by 12 head and neck-specific items to assess head and neck related 
symptoms, and form the FACT-Head and Neck Subscale (HNS). Each item is rated on a 
0 to 4 Likert type scale, and then combined to produce subscale scores for each domain, 
as well as a global QoL score. Higher scores represent better quality of life. 
Ten items of the FACT-H&N also form a symptom related index, FHNSI-10, which can 
be analyzed separately.22


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10.2.2.
EuroQoL-5 Dimensions-5 Levels Instrument
The EQ-5D-5L is a preference based measure of health status that is now widely used in 
clinical trials, observational studies, and other health surveys.23,24
The EQ-5D-5L consists of 2 pages – the EQ-5D-5L descriptive system and the EuroQoL
Visual Analogue scale (EQ VAS).The descriptive system comprises the following 5 
domains: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each 
domain has 5 levels: no problems, slight problems, moderate problems, severe problems, 
and extreme problems. The respondent is asked to indicate his/her health state by ticking 
(or placing a cross) in the box with the most appropriate statement in each of the 5 
domains. This decision results in a 1-digit number expressing the level selected for that 
domain. The digits for 5 domains can be combined in a 5-digit number or profile 
describing the respondent’s health state. It should be noted that the numerals 1-5 have no 
arithmetic properties and should not be used as a cardinal score. Patient preferences or 
utilities can be assigned to the health profiles from country-specific patient value sets for 
the calculation of quality adjusted life years which are applied in economic evaluation 
(cost-utility analysis).
The EQ VAS records the respondent’s self-rated health on a 20 cm vertical, visual 
analogue scale with endpoints labeled ‘the best health you can imagine’ and ‘the worst 
health you can imagine’. This information is used as a quantitative measure of health as 
judged by the individual respondents. The instructions for the EQ VAS asks respondents 
to ‘mark an X on the scale to indicate how your health is TODAY’ and then to ‘write the 
number you marked on the scale in the box below.’


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11.
STATISTICAL METHODS
11.1.
Analysis Sets
In addition to the analysis sets described below, the PK analysis set, and the PRO 
analysis set will be defined in the SAP.
11.1.1.
Full Analysis Set
The full analysis set (FAS) will be based on the intention-to-treat principle and will 
comprise all subjects randomized into the study. This set will contain HRG high stratum 
and HRG low stratum. Subjects will be analyzed as randomized.
11.1.2.
Per-Protocol Analysis Set
The per-protocol analysis set will include all subjects in the FAS who have completed at 
least 1 cycle of treatment, and who were sufficiently compliant with the protocol and 
without major protocol violation. Full criteria for defining sufficient compliance will be 
finalized and documented prior to database unblinding.
11.1.3.
Safety Analysis Set
The safety analysis set includes all subjects who received any amount of study 
medication.  Subjects will be analyzed according to actual treatment received. All safety 
analyses will be performed on the safety analysis set. Key safety data will also be 
summarized for HRG-high stratum. Key safety endpoints include frequency and severity 
of treatment-emergent adverse events (TEAEs) and incidence of HAHA development in 
relation to the TEAEs.
11.2.
General Statistical Considerations
This is a multicenter randomized Phase 2 study designed to evaluate the safety and 
efficacy of patritumab in combination with cetuximab and platinum-based therapy in 
recurrent/metastatic first-line SCCHN. The primary analyses for this study will occur 
when at least 53 PFS events have been observed in the HRG high stratum. 
At the point of primary analysis for PFS, the treatment assignment for all randomized 
subjects will be unblinded to designated study personnel for the analysis after data are 
reconciled and cleaned and a snapshot of the clean database is created.  To minimize 
potential bias, subjects and Investigators will not be informed about individual treatment 
assignment until study closure.
Final analyses will occur after study closure with mature OS data for the main study 
phase. At the time of study closure, subjects who are demonstrating clinical benefit (SD 
or better) from study treatment may be offered an opportunity to continue study treatment 
on the extension phase. 
Assessments of change from baseline to post baseline or the ratio of post baseline to 
baseline will include only those subjects with both baseline and post baseline 


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measurements.  The last nonmissing value of a variable taken before the first dose of 
study drug will be used as the baseline value, unless otherwise specified.  In general, 
missing or dropout data will not be imputed for the purpose of data analysis.  Descriptive 
summary statistics (n, mean, median, standard deviation, and range) will be calculated for 
continuous variables, and for categorical variables, the number and percentage in each 
category will be displayed by treatment group.
A detailed SAP describing the methodology will be prepared and finalized prior to 
primary analyses being performed and prior to database unblinding.  Statistical methods 
described here may be modified based on advances in research.  Any deviations and 
reasons for changes from the planned statistical analyses in the protocol will be fully 
described in the SAP and in the clinical study report.
11.3.
Study Population Data
Disposition and reasons for ending the treatment and discontinuing from the study and 
subsequent anticancer therapy will be listed and summarized in the FAS.
Demographic and baseline characteristics such as age, race, and baseline ECOG 
performance status, histology subtype, HRG value, and cancer type will be summarized 
by treatment group and overall for the FAS as well as the HRG-high stratum of the FAS, 
per-protocol analysis set, and safety analysis set.  If two sets of subjects are identical to 
each other, analysis will only be performed once.
Study drug exposure, treatment duration, and compliance with study therapy will be 
summarized using descriptive statistics by treatment group for the safety analysis set.
11.4.
Efficacy Analyses
Efficacy analyses will be performed on the FAS and per-protocol analysis set. Subjects 
will be analyzed according to the treatment assigned at randomization.
11.4.1.
Primary Efficacy Analyses
The primary efficacy endpoint for this study is PFS.  Progression free survival is defined 
as the time from the date of randomization to the earlier of the dates of the first objective 
documentation of radiographic disease progression (as per RECIST Version 1.1- see 
Appendix 17.3) or death due to any cause.  Subjects who are alive with no objective 
documentation of (radiographic) disease progression by the data cutoff date for PFS 
analysis will be censored at the date of their last evaluable tumor assessment.  Detailed 
censoring rules for PFS analysis will be specified in the SAP.
The primary analysis is PFS comparison between the patritumab arm and the control arm 
in HRG-high stratum of the FAS. The testing hypotheses to compare PFS between the 
patritumab arm versus the control arm will be performed in two steps.25 In step 1, the 
null hypothesis that PFS is the same for both arms in the HRG high stratum of FAS is 
tested at the one-sided 0.10 significance level. If this test in step 1 does not reject the null 
hypothesis, then in step 2A, the null hypothesis that PFS is the same for both arms in the 
FAS will be tested at the one-sided 0.05 significance level. If the test in step 1 is rejected, 
then in step 2B, the two-sided 80% confidence interval (CI) for hazard ratio (HR) of PFS 


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in the HRG low stratum of the FAS will be estimated. The results from both steps (PFS 
comparison in HRG-high stratum, and PFS comparison in FAS or PFS estimate in HRG-
low stratum) will be used to guide the decision on future Phase 3 designs.
The comparison of PFS between the patritumab arm and the control arm will be 
performed using a log-rank test stratified by the stratification factors in both the FAS and 
the HRG high stratum of FAS. The stratification factors include HPV (positive vs other) 
and HRG (high vs. low, only for the FAS) at randomization. Kaplan-Meier methods will 
be used to calculate median PFS and CIs and generate Kaplan-Meier curves for PFS. 
Estimates of HR between 2 arms along with their two-sided 80% and 95% CIs will be 
calculated using stratified Cox’s proportional hazards regression model. The model will 
include the treatment group as a covariate and the stratification factors used at 
randomization as strata.
The above analysis for PFS will be performed in the per-protocol analysis set.
11.4.2.
Secondary Efficacy Analyses
Secondary efficacy variables include OS and ORR (CR and PR). Overall survival is 
defined from the date of randomization to death due to any cause and will be analyzed in 
the same manner as for PFS. Subjects who are alive at the time of data cut off for OS
analysis will be censored at the last contact date at which the subject is known to be alive.  
Objective response rate is defined as the proportion of subjects with the best overall 
response of CR or PR. A confirmation of CR/PR is not required for this study as per 
RECIST Version 1.1. The differences in the ORR and OS between the control arm and 
patritumab arm will be presented along with two-sided 80% and 95% CIs based on the 
Wilson’s score method with continuity correction. These analyses will be done using the 
FAS for HRG high and low strata.  
11.4.3.
Exploratory Efficacy Analyses
Exploratory efficacy endpoints include duration of response, time to response, time to 
disease progression, and duration of SD. Exploratory efficacy endpoints and details of 
corresponding analyses will be defined in the SAP.
11.5.
Pharmacokinetic/Pharmacodynamic Analyses
11.5.1.
Pharmacokinetic Analyses
Serum concentrations for patritumab, cetuximab, and cisplatin/carboplatin will be 
displayed in tables of individual values and aggregated by treatment group in summary 
tables with descriptive statistics. To explore possible drug-drug interactions between 
patritumab plus cetuximab or cisplatin/carboplatin, the PK of serum cetuximab and 
platinum concentrations will be compared with and without patritumab. For all subjects, 
sparse samples for serum patritumab concentrations will be assessed using population PK 
methods. The relationship between exposure and response will be explored using 
population PK modeling.


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11.5.2.
Pharmacodynamic Analyses
Not Applicable
11.5.3.
Biomarker and Exploratory Analyses
The study has baseline HRG and HPV status biomarker assessments to determine the 
stratification factors of HRG and HPV. Baseline HRG cutoff will be used for all specified
efficacy analyses. As exploratory analyses, the HRG cutoff will be refined using graphic 
technique, data distribution, maximum likelihood methods, and clinical benefit of 
HRG-high group. Selected efficacy analyses for the HRG high stratum will be performed 
using the refined HRG cutoff as additional exploratory analyses. Further biomarker 
evaluations will be summarized descriptively.
11.6.
Safety Analyses
Safety analyses will be performed using the safety analysis set, and subjects will be 
analyzed according to their actual treatment received.  Key safety analyses will also be 
performed for HRG high stratum of the safety analysis set. Safety analyses in general will 
be descriptive and will be presented in tabular format with the appropriate summary 
statistics by treatment group. Listings of safety data will be presented using the safety 
analysis set.
11.6.1.
Adverse Event Analyses
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment, or reemerges during treatment, having been present at baseline but stopped 
prior to treatment, or worsens in severity since treatment relative to the pretreatment 
state, when the AE is continuous.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized for the number and percentage of subjects reporting 
treatment emergent AEs.  AEs/toxicities and laboratory test results (hematology and 
blood chemistry) will be graded according to the NCI CTCAE, Version 4.03. The number 
and percentage of subjects reporting TEAEs will be tabulated by the worst CTCAE 
grade, system organ class, and preferred term, with a breakdown by treatment group.  
Similarly, the number and percentage of subjects reporting treatment emergent SAEs will 
be tabulated, as well as TEAEs and treatment emergent SAEs considered related to 
patritumab, cetuximab, and cisplatin/carboplatin.
A by-subject AE (including treatment emergent) data listing including, but not limited to, 
verbatim term, preferred term, system organ class, CTCAE grade, and relationship to 
study drug will be provided.
SAEs reported from tumor biopsies collected during Screening will be recorded, but not 
included in the primary analysis.  
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation from patritumab, cetuximab, and cisplatin/carboplatin of a subject, will 
be listed.


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11.6.2.
Clinical Laboratory Evaluation Analyses
Clinical laboratory data and their changes from baseline (only for continuous laboratory 
parameters) will be summarized by treatment group and visit (including the maximum 
and minimum post-treatment values and the values at the End of Treatment visit).  
Summary tables will be presented for each relevant assay to show the number of subjects 
by CTCAE severity grade with corresponding percentages.  For parameters for which a 
CTCAE scale does not exist, the frequency of subjects with values below, within, and 
above the normal ranges will be summarized by treatment.  Subjects will be characterized 
only once for a given assay, based on their worst severity grade observed during the time 
period of interest. Shift tables for clinical laboratory data will also be presented showing 
change in CTCAE severity grade from baseline to each visit (and to the minimum, 
maximum, and last post-baseline values) for each treatment. 
Laboratory test results (hematology and blood chemistry) will be graded according to the 
NCI CTCAE, Version 4.03. A shift table, presenting the two-way frequency tabulation 
for baseline and the worst post-treatment value according to the CTCAE grade, will be 
provided for clinical laboratory tests. Abnormal clinical laboratory test results deemed of 
clinical significance or of Grade 3 or 4 will be listed.
11.6.3.
Vital Sign Analyses
Descriptive statistics will be provided for vital signs data and their changes from baseline 
will be summarized by treatment group and visit (including the maximum and minimum 
post-treatment values and the values at the End of Treatment visit).
11.6.4.
Electrocardiogram Analyses
The ECG parameters (PR, RR, QRS, heart rate-corrected QT interval by Bazett’s or by 
Fridericia’s formula) [QT, QTcB and QTcF]) will be summarized using descriptive 
statistics for actual values and for changes from baseline by treatment group by scheduled 
time of evaluation including end of treatment visit as well as for the maximum post 
treatment values.
The incidence of outliers in maximum absolute QTcF and QTcB intervals (> 450 > 480 
and > 500 msec) and the maximum absolute uncorrected QT intervals (> 500 msec) over  
end-of-treatment evaluation, as well as in QTcF and QTcB maximum changes from 
baseline (> 30 and > 60 msec) over end-of-treatment evaluation will be summarized by 
treatment.  A listing of ECG data will be provided.
11.6.5.
Physical Finding Analyses
A listing of physical examination findings will be provided.
11.6.6.
Other Safety Analyses
Key safety endpoints include frequency and severity of treatment-emergent AEs and 
incidence of human antihuman antibody HAHA development in relation to the TEAEs. 
HAHA findings from all subjects will be listed to identify subjects with positive HAHA 
findings and when the earliest positive HAHA findings were observed for these subjects.


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Echocardiogram or MUGA data will be listed.
11.7.
Other Analyses
11.7.1.
Patient Reported Outcomes
Descriptive statistics will be computed for the specified PRO measures, the FACT-H&N 
(total score, subscales including the HNS, and individual symptom items) and FHNSI-10, 
by scheduled time of evaluation and by treatment as well as the change from baseline.  
Best response (improvement, stability, or deterioration) on each of the above PROs based 
upon published classification of responses on the same PROs will be compared between 
the patritumab and control arms.  In addition, this study will also present the entire 
cumulative distribution of change from baseline in specified PROs as a continuous plot of 
the change from baseline on the X-axis and the cumulative percent of patients 
experiencing that change on the Y axis for the patritumab and control arms, as 
recommended in the recent FDA final guidance on PROs.  Based upon the entire 
cumulative distributions, various categorical distributions of best responses representing 
alternative magnitudes of change from baseline as criteria for classification of responses 
will also be presented across treatment groups, as appropriate.
Change from baseline of the PRO measures will also be evaluated using mixed 
longitudinal modeling with treatment, time, and treatment-by-time interactions as fixed 
effects, subject as random effect, and baseline PRO score as covariate.  Differences 
between the control arm and patritumab arm will be presented along with 95% CIs.  
These analyses on PRO measures will be considered as exploratory and further details of 
all analyses, including handling of missing data, will be described in the SAP.
Descriptive statistics for the actual value and change from baseline will be computed for 
the EQ-5D-5L health profile utilities and EQ-5D VAS by scheduled time of evaluation 
(including end of treatment visit) for all subjects and by treatment group.  Results of the 
EQ VAS will be presented as a measure of overall self-rated health status.  Further details 
of analyses will be provided in the SAP.
11.7.2.
Eastern Cooperative Oncology Group
ECOG performance status at baseline will be summarized.  A shift table, presenting the 
two way frequency tabulation for baseline and end of study treatment visit, will be 
provided for ECOG performance status.
11.8.
Interim Analyses
No interim analysis is planned
11.9.
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be established for this study 
and will review the ongoing safety of the study participants and monitor the overall 
conduct of the clinical trial. The DMC will review accumulating safety data when at least 
25% of the target number of subjects is enrolled after the first subject is randomized.
Subsequent DMC meetings will convene as needed until database lock. Based on its 


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ongoing review of the unblinded safety data, the DMC will outline any serious safety 
concerns and make recommendations to continue, modify, suspend, or terminate the 
study.
Details on the membership, responsibilities and working procedures of the Independent
DMC will be described in the DMC Charter, provided as a separate document in the
study file. The same independent Data Analysis Group statistician responsible for 
providing the safety data will also provide efficacy data (for proper assessment of the
risk/benefits of continuing treatment and study) to the DMC for review.
11.10.
Sample Size Determination
The primary efficacy endpoint is PFS. The sample size for this study is based on the 
number of required PFS events in the HRG-high stratum. For PFS, a clinically 
meaningful improvement is defined as 79% increase from median PFS of 4.2 months in 
the control arm26 to median PFS of 7.5 months in the patritumab arm (that is a HR of 
0.56). A total of 70 HRG-high subjects will be randomized to observe 53 PFS events in 
the HRG high stratum assuming a one-sided alpha of 0.10, 80% power, and a 1:1 
randomization ratio between 2 arms, a 12-month enrollment and 10-month follow-up, 
and 10% dropouts. 
Under 2:1 (HRG high vs. low) stratification, a total of approximately 105 subjects 
(70 HRG high subjects and 35 HRG low subjects) will be randomized in both strata to 
observe at least 75 PFS events. The sample size from both strata combined will provide 
approximately 81% power to detect a HR=0.56 in PFS assuming one-sided alpha of 0.05 
and other same assumptions above. 
The sample size computation is performed using the test based on Survival Superiority 
Trials: Two Sample Test – Logrank Test: Given Accrual Duration and Study Duration in 
the EAST software (version 5.3, Cytel Inc.).


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12.
DATA INTEGRITY AND QUALITY ASSURANCE
The Investigator/investigational site will permit study-related monitoring, audits, 
IRB/IEC review and regulatory inspections by providing direct access to source 
data/documents.  Direct access includes permission to examine, analyze, verify, and 
reproduce any records and reports that are important to the evaluation of a clinical study.
12.1.
Monitoring and Inspections
The Sponsor/CRO monitor and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study (eg, eCRFs, source data, and 
other pertinent documents).
The monitor is responsible for visiting site(s) at regular intervals (see study monitoring 
plan for frequency of monitoring visits) throughout the study to verify adherence to the 
protocol; completeness, accuracy, and consistency of the data; and adherence to 
ICH GCP and local regulations on the conduct of clinical research.  The monitor is 
responsible for inspecting the CRFs and ensuring completeness of the study essential 
documents.  The monitor should have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs.
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action designed to prevent 
recurrence of the detected deviations is taken and documented.
The Investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are addressed and documented.
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from Sponsor.  Inspection of site facilities (eg, pharmacy, 
drug storage areas, laboratories, etc) and review of study related records will occur in 
order to evaluate the study conduct and compliance with the protocol, SOPs, ICH GCP, 
and applicable regulatory requirements.
12.2.
Data Collection
All relevant observations and data related to the study, as per the study protocol, will be 
recorded on eCRF pages.  A representative of Daiichi Sankyo or their designee will 
provide instruction for completing the eCRF.  Adequate and accurate case records should 
be maintained, including the evaluation of inclusion and exclusion criteria, medical 
history, physical examinations, clinical assessments, a record of clinical safety laboratory 
sample collection, drug administration, AEs, and final evaluation.  
The eCRFs must be completed for each subject who signs the ICF and undergoes 
screening procedures.  For subjects who are screened but not randomized, minimal data 
will be recorded on the eCRF, including demography, subject status, and AEs.  All study 
related data for these subjects will be maintained in the medical records at the site.


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12.3.
Data Management
Each subject will be identified in the database by a unique subject identifier as defined by 
the sponsor.
To ensure the quality of clinical data across all subjects and sites, a Clinical Data 
Management review will be performed on subject data according to specifications given 
to the Sponsor or designee.  Data will be vetted both electronically and manually for 
eCRFs the data will be electronically vetted by programmed data rules within the 
application.  Queries generated by rules and raised by reviewers will be generated within 
the Electronic Data Capture application.  During this review, subject data will be checked 
for consistency, omissions, and any apparent discrepancies.  
Data received from external sources such as central labs will be reconciled to the clinical 
database.
All data generated from external sources (i.e., central laboratory, 
pharmacokinetic processing, pharmacodynamics processing, and genotyping laboratory, 
etc.) will be integrated with the subject’s eCRF data in accordance with the Data 
Management Plan.
Serious AEs in the clinical database will be reconciled with the safety database.
All AEs will be coded using MedDRA.  
All concomitant medications and prior cancer therapies will be coded using the World 
Health Organization Drug Reference List Dictionary.
12.4.
Study Documentation and Storage
The Investigator will maintain a Signature List of appropriately qualified persons to 
whom he/she has delegated study duties.  All persons authorized to make entries and/or 
corrections on CRFs will be included on the Signature List.
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical and 
office charts, laboratory and pharmacy records, diaries, microfiches, X-rays, and 
correspondence.
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system (Trial Master File) of all study-related (essential) 
documentation, suitable for inspection at any time by representatives from the Sponsor
and/or applicable regulatory authorities.  Essential documents include (but are not limited 
to):

Subject files containing completed CRFs, informed consents, and supporting 
copies of source documentation (if kept)

Study files containing the protocol with all amendments, Investigator’s 
Brochure, copies of relevant essential documents required prior to 
commencing a clinical study, and all correspondence to and from the IEC/IRB 
and the Sponsor


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
Records related to the Investigational Product(s) including acknowledgment 
of receipt at site, accountability records and final reconciliation and applicable 
correspondence
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available.
All essential documentation will be retained by the Investigator until at least 2 years after 
the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have 
lapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period, however, if required by 
the applicable regulatory requirements or by an agreement with the sponsor.  It is the 
responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
No study document should be destroyed without prior written agreement between 
Sponsor and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify Sponsor in writing of 
the new responsible person and/or the new location.
12.5.
Record Keeping
Records of subjects, source documents, monitoring visit logs, data correction forms, 
CRFs, inventory of study product, regulatory documents (eg, protocol and amendments, 
IRB/IEC correspondence and approvals, approved and signed informed consent forms, 
Investigator’s Agreement, clinical supplies receipts, distribution and return records), and 
other sponsor correspondence pertaining to the study must be kept in appropriate study 
files at the site.  Source documents include all recordings and observations or notations of 
clinical activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical study.  These records will be retained in a secure file for the 
period required by the institution or site policy.  Prior to transfer or destruction of these 
records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records.


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13.
FINANCING AND INSURANCE
13.1.
Finances
Prior to starting the study, the Principal Investigator and/or Institution will sign a clinical 
study agreement with Sponsor or a CRO.  This agreement will include the financial 
information agreed upon by the parties.
13.2.
Reimbursement, Indemnity, and Insurance
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on 
terms agreed upon by the parties.


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14.
PUBLICATION POLICY
A study site may not publish results of a study until after a coordinated multicenter 
publication has been submitted for publication or until one year after the study has ended, 
whichever occurs first.  Therefore, the study site will have the opportunity to publish the 
results of the study, provided that Daiichi Sankyo has had the opportunity to review and 
comment on the study site’s proposed publication prior to its being submitted for 
publication with the prior advice of Daiichi Sankyo Legal Affairs (intellectual property 
council) and with proper regard to the protection of subjects’ identities.


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15.
STUDY ADMINISTRATIVE INFORMATION
15.1.
Protocol Amendments
Any amendments to the study protocol as the study progresses will be communicated to 
the investigator by the Sponsor.  All protocol amendments will undergo the same review 
and approval process as the original protocol.  A protocol amendment may be 
implemented after it has been approved by the IRB/IEC, unless immediate 
implementation of the change is necessary for subject safety.  In this case, the situation 
must be documented and reported to the IRB/IEC within five working days.  The sponsor 
will assure the timely submission of amendments to regulatory authorities.
15.2.
Address List
A list of key study personnel (including personnel at the sponsor, CRO, laboratories, and 
other vendors) and their contact information will be kept on file and updated in the Study 
Operations Manual.
15.2.1.
Sponsor
United States
Daiichi Sankyo, Inc.
399 Thornall Street 
Edison, NJ 08837, United States
15.2.1.1.
Sponsor Medical Monitor
 MD 
 
Daiichi Sankyo, Inc.
399 Thornall Street 
Edison, NJ 08837, United States
Phone:
Mobile: 
Fax: +
Email: 
15.2.1.2.
Sponsor Clinical Operations Delivery Lead 
 MBA
Daiichi Sankyo, Inc.


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399 Thornall Street
Edison NJ 08837, United States
Tel: 
Fax: 
Email:
15.2.1.3.
CRO Medical Monitor
Munich, Germany
Tel 
Mobile: 
566
Fax: 
15.2.1.4.
CRO Project Manager
 MD, CPM, PMP
 
 Maidenhead, SL6 3QH, UK 
Phone: 
Mobile: 
15.2.1.5.
Drug Safety
Maidenhead, UK
Phone: 
Fax -
15.2.2.
Sponsor
15.2.2.1.
Data Management
Please refer to the Study Manual.


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15.2.2.2.
Biological Specimens
Please refer to the Laboratory Manual.
15.2.2.3.
Interactive Web/Voice Response System (IxRS)
Please refer to the Study Manual.
15.2.2.4.
Pharmacogenomics Laboratory
Please refer to the Laboratory Manual.
15.2.2.5.
Bioanalytical Laboratory (PK and HAHA)
Please refer to the Laboratory Manual.


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16.
REFERENCES
                                                
1
Investigator’s Brochure—Anti-HER3 Antibody, Patritumab (U3-1287), Version 8.0. 
Daiichi Sankyo, 02 October 2015.
2
Anti-proliferative effect of patritumab (U3-1287) in combination with cetuximab. 
Research Study Report No. RR20140120-3. U3 Pharma GmbH. June 27, 2014.
3
Shames DS, Carbon J, Walter K, et al. High hergulin expression is associated with 
activated HER3 and may define an actionable biomarker in patients with squamous 
cell carcinomas of the head and neck. PLOS ONE. 2013;8:e56765.
4
Li C, Brand TM, Iida M, et al. Human epidermal growth factor receptor 3 (HER 3) 
blockade with U3-1287/AM888 enhances the efficacy of radiation therapy in lung 
and head and neck carcinoma. Discovery Medicine. 2013;16:79-92
5
Schneider M, Wenzl C, Kallus H, et al. Efficacy of patritumab (U3-1287), a fully
human anti-human epidermal growth factor receptor 3 (HER3) monoclonal antibody, 
in head and neck cancer models. Poster presented at: Annual Meeting of European 
Society of Medical Oncology. September 26-30, 2014. Madrid, Spain.
6
Deng Z, Hasegawa M, Aoki K, et al. A comprehensive evaluation of human 
papillomavirus positive status and p16 overexpression as a prognostic biomarker in 
head and neck squamous cell carcinoma. Intl J Oncol. 2014;45:67-76.
7
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality 
worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 
2015;136:E359-E389. 
8
Gregoire V, Lefebvre J-L, Licitra L, Felip E, for the  EHNS-ESMO-ESTRO 
Guidelines Working Group. Squamous cell carcinoma of the head and neck: EHNS-
ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 
Ann Oncol. 2010;21 (Suppl  5): v184-v186.
9
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, et al. 
Platinum-Based Chemotherapy plus Cetuximab in Head and Neck Cancer. N Engl J 
Med. 2008;359:1116-27.


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10
Bourhis J, Rivera F, Mesia R, et al. Phase I/II study of cetuximab in combination with 
cisplatin or carboplatin and fluorouracil in patients with recurrent or metastatic 
squamous cell carcinoma of the head and neck. J Clin Oncol. 2006;24:2866-72.
11
Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus 
fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer 
(E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin 
Oncol. 2005;23:3562-67.
12
Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing 
cisplatin and fluorouracil as single agents and in combination for advanced squamous 
cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257-62.
13
Tribius S, Kronemann S, Kilic Y, et al. Radiochemotherapy including cisplatin alone 
versus cisplatin + 5-fluorouracil for locally advanced unresectable stage IV squamous 
cell carcinoma of the head and neck. Strahlenther Onkol. 2009;185:675-81.
14
Gupta S, Khan H, Barik S, Negi MP. Clinical benefits of concurrent capecitabine and 
cisplatin versus concurrent cisplatin and 5-flourouricil in locally advanced squamous 
cell head and neck cancer. Drug Discov Ther. 2013;7:36-42.
15
Recommendations related to contraception and pregnancy testing in clinical trials. 
Advisory non-binding guidance supported by national competent authorities 
represented at the CTFG-meeting in Rome 2014-09-15.
16
Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
Food and Drug Administration Web Site. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/G
uidances/UCM072278.pdf. Accessed February 7, 2014.
17
ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994.
18
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol. 1982;5:649 55.
19
Cella DF. Manual: Functional Assessment of Cancer Therapy (FACT) Scales and 
Functional Assessment of HIV Infection (FAHI) Scale. Chicago: Rush-Presbyterian-
St. Luke's Medical Center (1994).


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20
Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy 
scale: development and validation of the general measure. J Clin Oncol. 
1993;11:570-9.
21
D'Antonio LL, Zimmerman GJ, Cella DF, & Long, S.A. Quality of life and functional 
status measures in patients with head and neck cancer. Arch Otolaryngol Head Neck 
Surg. 1996; 122, 482-487.
22
Yount S, List M, Du H, et al. A randomized validation study comparing embedded 
versus extracted FACT head and neck symptom index scores. Qual Life Res. 
2007;16:1615-26.
23
The EuroQol Group (1990). EuroQol-a new facility for the measurement of health-
related quality of life. Health Policy. 1990;16(3):199-208.
24
Brooks R. EuroQol: the current state of play. Health Policy. 1996; 37(1):53-72.
25
Freidlin B, McShane LM, Polley M-Y C, et al. Randomized phase III trial designs 
with biomarkers. J Clin Oncol. 2012;30:3304-3309.
26
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA, for the Eastern 
Cooperative Oncology Group. Phase III randomized trial of cisplatin plus placebo 
compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: 
an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23:8646-54.


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17.
APPENDICES
17.1.
Modified Cockcroft-Gault Equation
The estimated serum creatinine clearance rate (CrCl; mL/min) will be calculated using 
the modified Cockcroft-Gault equationa based on actual weight, where weight is lean 
body mass in kilograms (1 kilogram = 2.2 pounds):
Conventional – serum creatinine in mg/dL:
Male:
CrCl (mL/min) = 
72
 x 
mg/dL)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
Female:
CrCl (mL/min) = 
72
 x 
mg/dL)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140
0.85
International System of Units (SI) – serum creatinine in μmol/L:
Male:
CrCl (mL/min) = 
0.0113
 x 
72
 x 
mol/L)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140

Female:
CrCl (mL/min) = 
0.0113
 x 
72
 x 
mol/L)
(in 
creatinine
serum
kg)
(in 
 x weight 
years)]
(in 
age
-
[140

0.85
                                                
a
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41.


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17.2.
Patient-Reported Outcomes
17.2.1.
Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N)
Note that the following questionnaire is provided as an example only of the FACT-H&N. 
Do not give this questionnaire to subjects for completion. Actual questionnaires to be 
given to subjects for completion will be provided under separate cover.


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17.2.2.
EuroQoL-5D-5L Health Questionnaire
Note that the following questionnaire is provided as an example only of the EQ-5D-5L
Health Questionnaire. Do not give this questionnaire to subjects for completion. Actual 
questionnaires to be given to subjects for completion will be provided under separate 
cover.


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17.3.
Assessment of Tumor Response
Assessment of tumor responses will be performed according to revised RECIST 
guidelines, Version 1.1. Some of these definitions and criteria are highlighted below.
17.3.1.
Measurement of Tumor at Baseline
17.3.1.1.
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows:
17.3.1.1.1. Measurements
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm).

10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable).

20 mm by chest X-ray.
Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm).  At baseline and in 
follow-up, only the short axis will be measured and followed.  See also notes below on 
‘Baseline documentation of target and non-target lesions’ for information on lymph node 
measurement.
17.3.1.1.2. Non-measurable
Non-measurable lesions: All other lesions, including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly 
non-measurable 
lesions. 
 
Lesions 
considered 
truly 
non-measurable 
include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin and lung, and abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques.
17.3.1.1.3. Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:
Bone Lesions

Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.  However, these techniques can be used 
to confirm the presence or disappearance of bone lesions


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
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such 
bas CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above

Blastic bone lesions are non-measurable
Cystic Lesions

Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above.  However, if noncystic lesions are present in the same subject, these 
are preferred for selection as target lesions
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected 
to other loco-regional therapy, are not considered measurable unless there has 
been demonstrated progression in the lesion since the therapy
17.3.1.2.
Specifications by Methods of Measurements
17.3.1.2.1. Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and NEVER more than 4 weeks before the beginning of the treatment.
17.3.1.2.2. Method of Assessment
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  Imaging-based 
evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam.
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for 
body scans).
                                                
b
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in 
solid tumours: revised  RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-247.


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17.3.2.
Tumor Response Evaluation
17.3.2.1.
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements.  In 
this study, only subjects with measurable disease at baseline should be included in the 
study.
17.3.2.2.
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions
When more than one measurable lesion is present at “baseline” all lesions up to a total of 
two lesions per organ and a maximum of five lesions total representative of all involved 
organs should be identified as target lesions and will be recorded and measured at 
baseline (this means in instances where subjects have only one or two organ sites 
involved a maximum of two and four lesions, respectively will be recorded).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance that the next largest lesion that can be measured reproducibly should be 
selected.
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an abdominal 
node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node.  In this example, 20 mm should be recorded as the node 
measurement.  All other pathological nodes (those with short axis ≥10 mm but <15 mm) 
should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.


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All other lesions (or sites of disease or nodes), including pathological lymph nodes, 
should be identified as non-target lesions and should also be recorded at baseline.  
Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’.  In addition, it is possible to record 
multiple non-target lesions involving the same organ as a single item on the case record 
form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).
17.3.2.3.
Response Criteria
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.
17.3.2.4.
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note: the appearance of one or 
more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study.
17.3.2.4.1. Special Notes on the Assessment of Target Lesions
Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
CR criteria are met, since a normal lymph node is defined as having a short axis of 
<10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions.
Target lesions that become ‘too small to measure’:  While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline become 
so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’.  When this occurs it is 
important that a value be recorded on the CRF.  If it is the opinion of the radiologist that 
the lesion has likely disappeared, the measurement should be recorded as 0 mm.  If the 
lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (Note: It is less likely that this rule will be used for 
lymph nodes since they usually have a definable size when normal and are frequently 


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surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well).  This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible; therefore, providing this 
default value will prevent false responses or progressions based upon measurement error.  
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment:  When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’.
17.3.2.5.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only qualitatively 
at the time points specified in the protocol.
CR: Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.
PD: Unequivocal progression (see comments below) of existing non-target lesions.  
(Note: the appearance of one or more new lesions is also considered progression).
17.3.2.5.1. Special Notes on Assessment of Progression of Non-target Disease
The concept of progression of non-target disease requires additional explanation as 
follows, when the subject also has measurable disease.  In this setting, to achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore, be extremely rare.
17.3.2.6.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 


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should be unequivocal: i.e., not attributable to differences in scanning technique, change 
in imaging modality or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions).  This is particularly important when the subject’s baseline lesions show partial 
or complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a ‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of 
this is the subject who has visceral disease at baseline and, while on study has a CT or 
MRI which reveals brain metastases.  The subject’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan that indicated its presence.
17.3.2.7.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment.  No confirmatory measurement for CR or PR is 
required in this study.
The subject’s best overall response assignment will depend on the findings of both target 
and non-target disease and will also take into consideration the appearance of new 
lesions.
17.3.2.7.1. Time Point Response
It is assumed that at each protocol-specified time point, a response assessment occurs. 
Table 17.1 provides a summary of the overall response status calculation at each time 
point for subjects who have measurable disease at baseline.


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Table 17.1:
Time Point Response: Subjects With Target (+/–Non-Target) Disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No 
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No 
PR
SD
Non-PD or not all 
evaluated
No 
SD
Not all Evaluated
Non-PD 
No
NE
PD  
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = Not Evaluable. 
17.3.2.7.2. Missing Assessments and Inevaluable Designation
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response.  This would be most likely to happen in the case 
of PD.  For example, if a subject had a baseline sum of 50 mm with three measured 
lesions and at follow-up only two lesions were assessed, but those gave a sum of 80 mm, 
the subject will have achieved PD status, regardless of the contribution of the missing 
lesion.
17.3.2.7.3. Best Overall Response: All Time Points
The best overall response is determined once all the data for the subject are known.
Best response determination in trials where confirmation of CR or PR IS NOT required: 
Best response in these trials is defined as the best response across all time points (for 
example, a subject who has SD at first assessment, PR at second assessment, and PD on 
last assessment has a best overall response of PR).  When SD is believed to be best 
response, it must also meet the protocol-specified minimum time from baseline, 6 weeks.  
If the minimum time is not met when SD is otherwise the best time point response, the 
subject’s best response depends on the subsequent assessments.  For example, a subject 
who has SD at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD.  The same subject lost to follow-up after the first SD 
assessment would be considered inevaluable.  


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17.3.2.7.4. Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression, should it be based on increase in size of the nodes.  As noted 
earlier, this means that subjects with CR might not have a total sum of ‘zero’ on the CRF.
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘clinical progression.’  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of 
an objective response: it is a reason for stopping study therapy.  The objective response 
status of such subjects is to be determined by evaluation of target and non-target disease.  
If a radiographic tumor assessment has not been performed within 4 weeks of the time of 
clinical progression, then another radiographic assessment should be performed without 
waiting for the next regularly scheduled scan. 
For equivocal findings of progression (i.e., very small and uncertain new lesions; cystic
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
17.3.2.8.
Frequency of Tumor Re-evaluation
In this study, tumor measurement will be conducted at Screening, and then at every 
6 weeks for the first 24 weeks. After 24 weeks, tumor assessments will be performed 
every 12 weeks, or sooner if clinically indicated. Tumor measurement will be performed 
during the end of treatment visit unless it was performed within the previous 6 weeks or 
the previous assessment demonstrated disease progression. 
Baseline tumor assessments must be performed within 2 weeks (14 days) prior to the first 
dose of treatment (Section 6.1.2). Existing radiographic scans can be used for the baseline 
evaluation if the scans were performed within 4 weeks prior to randomization.
All efforts should be made to ensure consistency between the baseline measurements and 
all subsequent measurements in reference to utilization of scanning method, equipment, 
technique (including slice thickness and field of view), and radiographic interpreter.
The radiographic evaluation must include CT or MRI scanning of the chest and abdomen.  
Any additional suspected sites of disease should also be imaged.  All evaluations should 
meet the standard of care for imaging of lesions in the respective organ(s) and should 
conform to the image acquisition guidelines according to institutional standards.
All target and non-target sites are evaluated at each time point of tumor assessment.


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17.4.
Schedule of Events


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Table 17.2:
Schedule of Events for Main Study
Assessment
Tissue 
screen
Screen
Random-
ization
Cycle 1 (Weeks 1-3)
Cycles 
2 & 3
Cycle 4 & 
all 
Subsequent 
Cycles
End of 
Cycle 6 
& Every 
4 Cycles
Every 
6 
weeks
End-of-
Study 
Treatment 
Visit
40 Days 
After 
Last 
Dosea
Day 1
Day 2 Day 3 Day 8 Day 15
Day 1
Day 1
Predose Dosing
EOI
Visit Window (Days)
-14 unless 
otherwise 
indicated
21 days 
after last 
dose a
Informed consent for 
tumor tissue
X
Informed consent (s) b
X
Medical history 
(including smoking 
history) & 
demographics
X
Inclusion / Exclusion 
X
Physical exam 
X
X
X
X
X*
X*
X
Vital signs 
X
X
X
X
X
X*
X*
X
Height & weight c
X
X d
X*d
X*d
Xd
ECOG
X
X
X
X
X
X
X
Echo or MUGA e
X
X e
X e
X
ECG (12-lead) e
X
X
Con Meds
X
X
X
X
X
X*
X*
X
Adverse Events
X f
X
X
X
X
X
X*
X*
X
X g
PRO assessments h
X
X
X
X
CBC differential & 
platelets i
X
X d
X d
X d
X* d
X* d
X d
Serum chemistries i
X
X d
X d
X d
X* d
X* d
X d
GFR or estimated 
serum creatinine 
clearance j
X
X
X
X
Coagulation
X
Urinalysis
X
X
IxRS
X
Intense PK k
X d
X
X
X
X
X
X†
Sparse PK (all) l
X d
X
X
X
HAHA sample l
X d
X
X
Pregnancy test m
X
X


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Assessment
Tissue 
screen
Screen
Random-
ization
Cycle 1 (Weeks 1-3)
Cycles 
2 & 3
Cycle 4 & 
all 
Subsequent 
Cycles
End of 
Cycle 6 
& Every 
4 Cycles
Every 
6 
weeks
End-of-
Study 
Treatment 
Visit
40 Days 
After 
Last 
Dosea
Day 1
Day 2 Day 3 Day 8 Day 15
Day 1
Day 1
Predose Dosing
EOI
Patritumab Adm n
X
X
X
Cetuximab Adm o
X
X
X
X
X
Platinum Adm p
X
X
X
PGx sample q
X d
Tumor assessments r
X
X s
X
Survival follow-up
X t
Additional biomarker 
blood samples u
X u
X u
X u
X u
X u
a Last dose of any study drug administered.
b Informed consent for main study (mandatory) and pharmacogenomics (optional).
c Height measured only at Screening.
d These assessments can be performed within 3 days prior to visit.
e Echocardiograms/MUGA scans will be performed at Screening, Cycle 3, at every third subsequent cycle, and End-of-Study Visit. Additional echocardiograms/MUGA
scans and electrocardiograms may be performed at the discretion of the investigator. The same test (echocardiogram or MUGA) must be used for a subject throughout 
the study.
f Collect SAEs only related to the biopsy procedure.
g At 40 days after the last dose of study drug, a telephone call will be placed to the subject to record adverse events.
h PRO assessments will be administered before any study-related procedures are performed.
i Results must be available prior to dosing.
j At Screening, either GFR or the estimated serum creatinine clearance (mL/min) as an estimate of GFR will be calculated. The estimated serum creatinine clearance rate 
(CrCl; mL/min) will be calculated using the modified Cockcroft-Gault equation (Appendix 17.1). The estimated GFR will also be calculated before each cisplatin or 
carboplatin administration. This will be performed only until completion of chemotherapy. 
k Intensive serum PK in a subgroup of 30 subjects samples will be collected. See Table 8.2 for detailed information on sampling times.
l See Table 8.1 for detailed information on sampling times.
mPregnancy test must be confirmed negative before dosing. Additional pregnancy testing may be done at the discretion of the Investigator and/or if required by local 
regulations for women of child-bearing potential.
n Patritumab administered initially at 18 mg/kg and thereafter 9 mg/kg every 3 weeks as a continuous intravenous infusion over 60 minutes ( ±10 minutes). Infusion 
times can be extended to a maximum of 120 minutes for subjects unable to tolerate the 60-minute infusion.
o Cetuximab infusions administered initially at 400 mg/m2 IV over 2 hours and 250 mg/m2 over 1 hour weekly. Cetuximab is administered 60 minutes after patritumab 
administration. Cetuximab is given on Days 1, 8, and 15.
p Cisplatin infusions administered at 100 mg/m2 IV over 1 hour and every 3 weeks up to a maximum of 6 cycles. For pre- and post-treatment hydration see Section
3.1.2.1 and according to institutional standards. Creatinine clearance required prior to cisplatin administration. Cisplatin administered 1 hour after cetuximab 
administration. If carboplatin is selected instead of cisplatin, administer carboplatin at AUC of 5 over 30-60 minutes every 3 weeks for a maximum of 6 cycles. See 
Section 3.1.2.1 for carboplatin.
q Genetic sampling is optional.


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r Tumor measurements will be assessed per RECIST Version 1.1. Baseline scans to be performed as part of eligibility during Screening. Existing radiographic scans can 
be used for the baseline evaluation if the scans were performed within 4 weeks prior to randomization.
s Tumor assessments are to be performed every 6 weeks to Week 24 (+/- 3 days), then every 12 weeks (+/- 7 days) thereafter.
t After discontinuation from study treatment, follow-up information for survival will be obtained per telephone approximately every 3 months for a minimum of 
13 months.
u Additional biomarker samples:
Collect blood sample for cfDNA predose Cycle 1 Day 1, predose Cycle 2 Day 1, End of Cycle 6,  predose every 4 Cycles, at progression (end of study treatment), and 
40 days after last dose of study drug administered. 
Collect blood samples for exosome at: predose Cycle 1 Day 1, predose Cycle 2 Day 1, and End of Cycle 6. Refer to the laboratory manual for instructions on collection 
and management of samples.
* Can be collected on Days 8 and 15 in all subsequent cycles at the discretion of the Investigator.
† Corresponds to Cycle 1, Day 21 (504 hrs)—see Table 8.2.


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Table 17.3:
Schedule of Events for Extension Phase
Additional cycles
Every 3 months
End of 
Treatment
40 days after 
last dosea
Predose
Dosing
Visit Window (Days)
Physical Exam
X
X
Vital Signs
X
X
Adverse Events
X
X
CBC diff and platelets b
X b
X b
Serum chemistries b
X b
X b
HAHA and PK sample c
X
Patritumab Adm d
X
Cetuximab Adm e
X
Additional  biomarker blood samples
X
X
X
a Last dose of any study drug administered.
b CBC and chemistries must be performed within 3 days of dosing.
c For subjects with positive HAHA at the End of Study Treatment visit, additional serum HAHA samples should be collected every 3 months up to 1 year from the last 
dose of study drug or if the subject starts another therapy for cancer, or withdraws consent from the study, whichever occurs first.
d Patritumab administered at 9 mg/kg every 3 weeks as a continuous intravenous infusion over 60 minutes (±10 minutes). Infusion times can be extended to a maximum 
of 120 minutes for subjects unable to tolerate the 60 minute infusion.
e Cetuximab is infused at 250 mg/m2 over 1 hour weekly. Cetuximab can be administered directly after patritumab administration.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
(SAP) 
 
RANDOMIZED, PLACEBO-CONTROLLED, 
DOUBLE-BLIND PHASE 2 STUDY OF 
PATRITUMAB (U3-1287) IN COMBINATION WITH 
CETUXIMAB PLUS PLATINUM-BASED THERAPY 
IN FIRST LINE SETTING IN SUBJECTS WITH 
RECURRENT OR METASTATIC SQUAMOUS 
CELL CARCINOMA OF THE HEAD AND NECK 
 
PROTOCOL U31287-A-U203 
 
VERSION 1.0, 29 NOVEMBER 2016 
 
Daiichi Sankyo, Inc. 
399 Thornall Street 
Edison, NJ 08837  
United States 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo Development Limited. 
The information is provided to you in confidence to enable you to perform the work, which is 
requested under an agreed upon and signed confidentiality statement.  Do not give this document 
or any copy of it or reveal any proprietary information contained in it to any third party (other 
than those in your organization who are assisting you in this work and are bound by the 
confidentiality statement) without the prior written permission of an authorized representative of 
Daiichi Sankyo Development Limited. 
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STATISTICAL ANALYSIS PLAN SYNOPSIS 
 
Protocol Number: 
U31287-A-U203 
Protocol Version and Date: 
VERSION 4.0 13 JUN 2016 
Name of Investigational 
Product: 
Patritumab (U3-1287) 
Study Title: 
Randomized, Placebo-Controlled, Double-Blind Phase 2 
Study of Patritumab (U3-1287) in Combination with 
Cetuximab plus Platinum-Based Therapy in First Line 
Setting in Subjects with Recurrent or Metastatic Squamous 
Cell Carcinoma of the Head and Neck 
Study Phase: 
Phase 2 
Study Objectives: 
Primary Objective 
 To evaluate progression-free survival (PFS) in the 
heregulin (HRG) high expression population from 
subjects treated with patritumab + cetuximab + 
platinum-based therapy compared to placebo + 
cetuximab + platinum-based therapy. 
Secondary Objectives 
 Evaluate overall survival (OS) 
 Evaluate overall response rate (ORR) 
 Refine the cutoff between heregulin high and low 
expression based on clinical data from this study 
 Assess the population PK of patritumab in subjects 
with Squamous cell carcinoma of the head and neck 
(SCCHN) 
 Assess the PK parameters of serum cetuximab and 
platinum concentrations when cetuximab and 
cisplatin or carboplatin (platinum-based therapy) 
are coadministered with patritumab in a sub group 
(n = 30) of subjects 
 Evaluate the incidence of human antihuman 
antibody (HAHA) formation (anti-patritumab 
antibodies) 
 Evaluate the safety and tolerability of the 
combination of patritumab + cetuximab + platinum-
based therapy in first-line treatment of subjects with 
SCCHN 
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Study Design: 
This is a multicenter, randomized, placebo-controlled, 
double blind Phase 2 study to evaluate the PFS and safety 
in recurrent/metastatic first-line SCCHN in subjects treated 
with patritumab plus cetuximab plus platinum-based 
therapy compared with subjects randomized to the control 
arm consisting of placebo plus cetuximab plus platinum-
based therapy. 
There will be two treatment arms stratified by HRG status 
(high and low): 
1. Patritumab + cetuximab + platinum-based therapy 
with HRG high and HRG low subjects 
2. Placebo + cetuximab + platinum-based therapy with 
HRG high and HRG low subjects 
Approximately 105 subje ts will be randomized to the 
patritumab and the control arms in a 2:1 stratification 
fashion between HRG high versus low strata 
(approximately 70 HRG-high and approximately 35 
HRG-low subjects). When one HRG stratum is filled with 
the required sample size, the enrollment in that HRG 
stratum will cease. The randomized subjects will also be 
further stratified 1:1 by HPV status (positive vs negative). 
The cut-off for HRG high versus low before randomization 
will be set using the median HRG value of commercial 
tissue samples. 
Number of Planned Study 
Centers: 
Approximately 35 sites in Europe. 
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Planned Sample Size: 
The primary efficacy endpoint is PFS. The sample size for 
this study is based on the number of required PFS events in 
the HRG-high stratum. For PFS, a clinically meaningful 
improvement is defined as 79% increase from median PFS 
of 4.2 months in the control arm to median PFS of 7.5 
months in the patritumab arm (that is a HR of 0.56). A total 
of 70 HRG-high subjects will be randomized to observe 53 
PFS events in the HRG high stratum assuming a one-sided 
alpha of 0.10, 80% power, and a 1:1 randomization ratio 
between 2 arms, a 12-month enrollment and 10-month 
follow-up, and 10% dropouts. 
Under 2:1 (HRG high vs. low) stratification, a total of 
approximately 105 subjects (70 HRG high subjects and 35 
HRG low subjects) will be r ndomized in both strata to 
observe at least 75 PFS events  The sample size from both 
strata combined will provide approximately 81% power to 
detect a HR=0.56 in PFS assuming one-sided alpha of 0.05 
and other same assumptions above. 
The sample size computation is performed using the test 
based on Survival Superiority Trials: Two Sample Test – 
Logrank Test: Given Accrual Duration and Study Duration 
in the EAST software (version 5.3, Cytel Inc.). 
Study Duration: 
For the purpose of collecting survival data, the duration of 
the study will be until all subjects have died or a minimum 
of 13 months after the last subject is randomized whichever 
comes first, approximately 22 months for PFS and 25 
months for OS. 
Subjects receiving clinical benefit from treatment will be 
offered the opportunity to continue therapy with patritumab 
and cetuximab (platinum-based therapy administered for no 
more than 6 cycles) in the extension phase of this protocol. 
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Summary of Eligibility 
Criteria: 
Key Inclusion Criteria 
1. Adult subjects ≥18 years old 
2. Histologically confirmed recurrent disease or metastatic 
SCCHN tumor and/or from its lymph nodal metastases 
originating from the oral cavity, oropharynx, 
hypopharynx, and larynx 
3. Heregulin expression level is required 
- Samples must be taken from subjects who have 
recurrent or metastatic disease. These samples can 
be from either rec/met archived or fresh biopsy 
samples 
- No cancer treatment between time of biopsy and 
submission of sample 
- Surgical or core needle biopsy is acceptable 
- Fine-needle aspiration or cytology is not acceptable 
for biopsies 
4. Human papilloma virus (HPV) status or p16 (surrogate 
for HPV) is required. These results must come from 
tumor tissue. These results may be obtained from either 
a local lab or samples sent to the central lab 
 HPV or p16 status can be from any tumor biopsy 
material from initial diagnosis 
5. Measurable disease per Response Evaluation Criteria in 
Solid Tumor (RECIST) Version 1.1 
6. Eastern Cooperative Oncology Group performance status 
0 or 1 
7. Hematological function, as follows: 
 Absolute neutrophil count ≥ 1.5 x 109/L 
 Platelet count ≥ 100 x 109/L 
 Hemoglobin ≥ 10 g/dL 
8. Renal function, as follows: 
 Estimated serum creatinine clearance (mL/min) or 
glomerular filtration rate (GFR) ≥ 60 mL/min for 
cisplatin and ≥ 30 mL/min for carboplatin 
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9. Hepatic function, as follows: 
 Aspartate aminotransferase ≤ 2.5 x upper limit of 
normal (ULN) (if liver metastases are present, < 5 x 
ULN) 
 Alanine aminotransferase ≤ 2.5 x ULN (if liver 
metastases are present, < 5 x ULN) 
 Alkaline phosphatase ≤ 2.0 x ULN (if bone or liver 
metastases are present, < 5 x ULN) 
 Bilirubin ≤ 1.5 x ULN 
10. Prothrombin time or partial thromboplastin time ≤ 1.5 x 
ULN 
11. Women of childbearing potential must have a negative 
serum pregnancy test performed within 14 days prior to 
enrollment (where demanded by local regulations, test 
may be required within 72 hours prior to enrollment) 
12. Adult subjects of child-bearing potential must agree to 
use double barrier contraceptive measures. Two of the 
following precautions must be used: bilateral 
vasec omy, bilateral tubal ligation, intrauterine device 
(IUD), combined (estrogen and progesterone 
containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal), 
progesterone-only hormonal contraception associated 
with inhibition of ovulation (oral, injectable, 
implantable), intrauterine hormonereleasing system 
(IUS), condom with spermicide, abstinence. These 
contraception measures must be used for the entire 
duration of the study and for 6 months after the last 
study dose is received 
13. Subjects must be willing and able to comply with 
schedule visits, treatment plan, laboratory tests, and 
other study procedures 
14. Provided written informed consent(s) 
Key Exclusion Criteria 
1. Left ventricular ejection fraction <50% 
2. Prior epidermal growth factor receptor targeted regimen 
3. No HRG expression result 
4. No HPV or p16 status 
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5. Prior anti-HER3 therapy 
6. Prior chemotherapy for recurrent/metastatic disease 
7. Anti-cancer therapy between biopsy and submission of 
sample 
8. Presence of squamous cell tumors of the nasopharynx 
9. History of other malignancies, except adequately treated 
non-melanoma skin cancer, curatively treated in-situ 
disease, or other solid tumors curatively treated with no 
evidence of disease for ≥ 2 years 
10. Known history of brain metastases or currently active 
brain metastases 
11. Uncontrolled hyperten ion (systolic > 160 mm Hg or 
diastolic > 100 mm Hg) 
12. Clinically significant electrocardiogram (ECG) changes 
13. Myocardial infarction within 1 year before enrollment, 
symptomatic congestive heart failure (New York Heart 
Association >Class II), unstable angina, or unstable 
cardiac arrhythmia requiring medication 
14. Platinum-containing drug therapy with radiotherapy 
less than 6 months before study drug treatment 
15  Therapeutic or palliative radiation therapy or major 
surgery within 4 weeks before study drug treatment. 
Radiation treatment to all sites of measureable disease 
unless progression is documented after radiation 
16. Participated in clinical drug trials within 4 weeks before 
study drug treatment. Current participation in other 
investigational procedures 
17. Uncontrolled infection requiring intravenous (IV) 
antibiotics, antivirals, or antifungals, known HIV 
infection, or active hepatitis B or C infection or 
undergoing medical treatment for infection 
18. Uncontrolled type 1 or 2 diabetes mellitus 
19. Known hypersensitivity or allergic reaction against any 
of the components of the trial treatment 
20. Pregnant, breastfeeding, or unwilling/unable to use 
acceptable contraception 
21. Residual toxicities ≥ Grade 1 from previous therapies 
that the Investigator determines would exclude 
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participation 
22. Psychological, social, familial, or geographical factors 
that would interfere with study participation or follow-
up 
23. Committed to an institution by virtue of an order issued 
either by judicial or administrative authorities 
24. Employee or immediate relative of an employee of the 
sponsor, CRO, the study center, or their affiliates or 
partners 
25. Receiving yellow fever vaccine or live attenuated 
vaccines (for subjects receiving carboplatin) 
26. Presence of hemorrhagic tumors (for subjects receiving 
carboplatin) 
27. Prophylactic use of phenytoin or fosphenytoin (for 
subjects receiving cisplatin or carboplatin) 
Primary Endpoint: 
The primary efficacy endpoint is PFS, defined as the time 
from the date of randomization to the earlier of the dates of 
the first objective documentation of radiographic disease 
progression (per RECIST v1.1 as assessed by investigator) 
or death due to any cause.  
Secondary Endpoint: 
 OS 
 Date of randomization to death due to any cause 
 Subjects alive at time of data cut off for OS 
analysis will be censored at the last contact date 
at which subject is known to be alive 
 ORR (CR and PR) 
 Proportion of subjects with the best ORR of 
complete response (CR) or partial response (PR) 
regardless of whether it is confirmed or 
unconfirmed 
 Pharmacokinetic parameters: AUC0-21d and Cmax at 
end of infusion (EOI) for serum patritumab, 
cetuximab, and platinum concentrations in a 
subgroup (approximately 30 subjects). 
 Population PK methods will be used to assess 
the sparse data for serum patritumab 
concentrations 
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 Safety 
 Treatment-emergent Adverse events 
 ≥ Grade 3 National Cancer Institute Common 
Terminology Criteria for Adverse Events 
version 4.03 
 Clinical lab evaluations 
 Myocardial function status (assessed by 
echocardiograms or multigated acquisition scan) 
 ECGs 
 Vital signs 
 Physical exams 
 Human anti-humanized antibody formation 
Stopping Criteria: 
NA 
Statistical Considerations: 
This is a multicenter randomized Phase 2 study designed to 
evaluate the safety and efficacy of patritumab in 
combination with cetuximab and platinum-based therapy in 
recurrent/metastatic first-line SCCHN. The primary 
analyses for this study will occur when at least 53 PFS 
events have been observed in the HRG high stratum. 
At th  point of primary analysis for PFS, the treatment 
assignment for all randomized subjects will be unblinded to 
designated study personnel for the analysis after data are 
reconciled and cleaned and a snapshot of the clean database 
is created. To minimize potential bias, subjects and 
Investigators will not be informed about individual 
treatment assignment until study closure. 
Final analyses will occur after study closure with mature 
OS data for the main study phase. At the time of study 
closure, subjects who are demonstrating clinical benefit 
[stable disease (SD) or better] from study treatment may be 
offered an opportunity to continue study treatment on the 
extension phase. 
Assessments of change from baseline to post baseline or 
the ratio of post baseline to baseline will include only those 
subjects with both baseline and post baseline 
measurements. The last nonmissing value of a variable 
taken before the first dose of study drug will be used as the 
baseline value, unless otherwise specified. In general, 
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missing or dropout data will not be imputed for the purpose 
of data analysis. Descriptive summary statistics (n, mean, 
median, standard deviation, and range) will be calculated 
for continuous variables, and for categorical variables, the 
number and percentage in each category will be displayed 
by treatment group. 
Statistical Analysis for the 
Primary Endpoint: 
The primary analysis is PFS comparison between the 
patritumab arm and the control arm in HRG-high stratum 
of the FAS. The testing hypotheses to compare PFS 
between the patritumab arm versus the control arm will be 
performed in two steps. In step 1, the null hypothesis that 
PFS is the same for both arms in the HRG high stratum of 
FAS is tested at the one sided 0.10 significance level. If 
this test in step 1 does not reject the null hypothesis, then in 
step 2A, the null hypothesis that PFS is the same for both 
arms in the FAS will be tested at the one-sided 0.05 
significance level. If the test in step 1 is rejected, then in 
step 2B, the two-sided 80% confidence interval (CI) for 
hazard ratio (HR) of PFS in the HRG low stratum of the 
FAS will be estimated. 
The comparison of PFS between the patritumab arm and 
the control rm will be performed using a log-rank test 
stratified by the stratification factors in both the FAS and 
the HRG high stratum of FAS. The stratification factors 
include HPV (positive vs other) and HRG (high vs. low, 
only for the FAS) at randomization. Kaplan-Meier methods 
will be used to calculate median PFS and CIs and generate 
Kaplan-Meier curves for PFS. Estimates of HR between 2 
arms along with their two-sided 80% and 95% CIs will be 
calculated using stratified Cox’s proportional hazards 
regression model. The model will include the treatment 
group as a covariate and the stratification factors used at 
randomization as strata. 
The above analysis for PFS will also be performed in the 
per-protocol analysis set. 
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Statistical Analysis for the 
Secondary Endpoints: 
Secondary efficacy variables include OS and ORR (CR and 
PR). Overall survival is defined from the date of 
randomization to death due to any cause and will be 
analyzed in the same manner as PFS. Subjects who are 
alive at the time of data cut off for overall survival analysis 
will be censored at the last contact date at which the subject 
is known to be alive. ORR is defined as the proportion of 
subjects with the best overall response of CR or PR 
regardless of whether it is confirmed or unconfirmed. The 
differences in the ORR between the control arm and 
patritumab arm will be presented along with two-sided 80% 
and 95% CIs based on the Wilson’s score method with 
continuity correction. These analyses will be done using the 
FAS for HRG high and low strata. 
Safety data will be analyzed descriptively. 
Serum concentrations for patritumab, cetuximab, and 
cisplatin/carboplatin will be displayed in tables of 
individual values and aggregated by treatment group in 
summary tables with descriptive statistics. To explore 
possible drug-drug interactions between patritumab plus 
cetuximab or cisplatin/carboplatin, the PK of serum 
cetuximab and platinum concentrations will be compared 
with and without patritumab. For all subjects, sparse 
samples for serum patritumab concentrations will be 
assessed using population PK methods. The relationship 
between exposure and response will be explored using 
population PK modeling. 
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GENERAL INFORMATION 
Name and Address of Sponsor: 
Daiichi Sankyo, Inc. 
399 Thornall Street 
Edison, NJ 08837 
United States 
Name and Address of the SAP Author: 
, PhD 
 
 
Princeton, NJ 08540 
Name and Address of the Sponsor Study 
Biostatistician: 
PhD 
Daiichi Sankyo, Inc. 
399 Thornall Street 
Edison  NJ 08837 
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TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN SYNOPSIS .............................................................4 
GENERAL INFORMATION .........................................................................................14 
TABLE OF CONTENTS ................................................................................................15 
LIST OF TABLES ...........................................................................................................19 
LIST OF FIGURES .........................................................................................................22 
LIST OF DATA LISTINGS ............................................................................................23 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................25 
1. 
SCOPE .....................................................
..................................................27 
2. 
STUDY OBJECTIVES .................................... .........................................28 
2.1. 
Primary Objectives .............................. ... .....................................................28 
2.2. 
Secondary Objectives ....................... ....
..................................................28 
2.3. 
Exploratory Objectives .....................
.........................................................28 
3. 
STUDY DESIGN ................. ........ ...............................................................30 
3.1. 
General Study Design and Plan ......................................................................30 
3.2. 
Study Population ......... ... .... .......................................................................37 
3.3. 
Randomization and Blinding ..........................................................................37 
3.3.1. 
Randomization ...
...... ..................................................................................37 
3.3.2. 
Blinding ... .
.........
................................................................................37 
3.3.2.1. 
Unblinding at Primary Analysis .....................................................................37 
3.3.2.2. 
Unblinding at Study Closure ..........................................................................38 
3.3.2.3. 
Emergency Unblinding ...................................................................................38 
3.4. 
Study Assessments..........................................................................................38 
4. 
SAMPLE SIZE DETERMINATION .........................................................39 
5. 
STUDY VARIABLES ..................................................................................40 
5.1. 
Efficacy Variables ..........................................................................................40 
5.1.1. 
Primary Efficacy Variable ..............................................................................40 
5.1.2. 
Secondary Efficacy Variables .........................................................................41 
5.1.2.1. 
Overall Survival (OS) .....................................................................................41 
5.1.2.2. 
Object Response Rate (ORR) .........................................................................42 
5.1.3. 
Exploratory Efficacy Variables ......................................................................42 
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5.1.3.1. 
Duration of Response .....................................................................................42 
5.1.3.2. 
Time to Response ...........................................................................................43 
5.1.3.3. 
Time to Disease Progression (TTP) ................................................................43 
5.1.3.4. 
Duration of Stable Disease (SD) .....................................................................43 
5.2. 
Safety Variables ..............................................................................................43 
5.2.1. 
Adverse Events ...............................................................................................43 
5.2.2. 
Clinical Laboratory Evaluations .....................................................................44 
5.2.3. 
Vital Signs ......................................................................................................44 
5.2.4. 
ECG ................................................................................................................44 
5.2.5. 
Physical Examinations .............................. ...................................................44 
5.2.6. 
Other Safety Variables ............................... ......
..........................................44 
5.3. 
Pharmacokinetic Variables ...................
....
.............................................45 
5.3.1. 
Concentration Data .......................... ....
..................................................45 
5.3.2. 
Pharmacokinetic (PK) Parameters ..
.........................................................45 
5.4. 
Pharmacodynamic (PD) Variables ...............................................................45 
5.5. 
Biomarkers ........................ ....... ..................................................................45 
5.6. 
Other Variables ............
.... ......................................................................46 
5.6.1. 
Eastern Cooperative Oncology Group Performance Status ............................46 
5.6.2. 
Patient Reported Outcomes . ..........................................................................46 
6. 
ANALYSIS SETS ..... ..................................................................................49 
6.1. 
Analysis Sets Definitions ................................................................................49 
6.1.1. 
Full Analysis Set .............................................................................................49 
6.1.2. 
Safety Analysis Set .........................................................................................49 
6.1.3. 
Per-Protocol Analysis Set ...............................................................................49 
6.1.4. 
Pharmacokinetic Analysis Set ........................................................................49 
6.1.5. 
Patient Reported Outcome Analysis Set .........................................................49 
6.2. 
Protocol Deviations ........................................................................................49 
6.3. 
Treatment Misallocations ...............................................................................49 
7. 
GENERAL STATISTICAL CONSIDERATIONS ...................................51 
7.1. 
Adjustment for Covariates ..............................................................................51 
7.2. 
Handling of Dropouts or Missing Data ..........................................................51 
7.3. 
Interim Analyses and Data Monitoring ..........................................................51 
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7.4. 
Multicenter Studies .........................................................................................52 
7.5. 
Multiple Comparisons/Multiplicity ................................................................52 
7.6. 
Examination of Subgroups .............................................................................52 
8. 
STATISTICAL ANALYSIS ........................................................................53 
8.1. 
Study Population Data ....................................................................................53 
8.1.1. 
Subject Disposition .........................................................................................53 
8.1.2. 
Protocol Deviations ........................................................................................53 
8.1.3. 
Demographic and Baseline Characteristics ....................................................53 
8.2. 
Efficacy Analyses ...........................................................................................54 
8.2.1. 
Analysis of Primary Efficacy Variables ... ...................................................54 
8.2.2. 
Analysis of Secondary Efficacy Variables ......
..........................................55 
8.2.2.1. 
Overall Survival ....................................
....
.............................................55 
8.2.2.2. 
Objective Response Rate ................. ....
..................................................55 
8.2.2.3. 
Cutoff for HRG Expression ............
.........................................................56 
8.2.3. 
Analysis of Exploratory Efficacy Variables ...................................................56 
8.2.3.1. 
Duration of Response ....... ....... ..................................................................56 
8.2.3.2. 
Time to Response ........
.... ......................................................................56 
8.2.3.3. 
Time to Disease Progression ..........................................................................56 
8.2.3.4. 
Duration of Stable Disease .. ..........................................................................56 
8.2.4. 
Sensitivity and Subgroup Analysis .................................................................56 
8.2.4.1. 
Sensitivity Analysis ........................................................................................56 
8.2.4.2. 
Subgroup Analysis ..........................................................................................57 
8.3. 
Safety Analyses ..............................................................................................58 
8.3.1. 
Adverse Events ...............................................................................................58 
8.3.2. 
Clinical Laboratory Evaluations .....................................................................59 
8.3.4. 
Vital Signs ......................................................................................................60 
8.3.5. 
ECG ................................................................................................................60 
8.3.6. 
Dosing and Extent of Exposure ......................................................................61 
8.3.7. 
Prior and Concomitant Medications ...............................................................62 
8.3.9. 
Analysis of Other Safety Variables ................................................................62 
8.4. 
Pharmacokinetic Analyses ..............................................................................63 
8.4.1. 
Concentration Data .........................................................................................63 
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8.4.1.1. 
Sparse Patritumab PK .....................................................................................63 
8.4.1.2. 
Intensive PK ....................................................................................................63 
8.4.2. 
Analysis of Pharmacokinetic (PK) Parameters ...............................................63 
8.4.3. 
Population Pharmacokinetic (PK) and Exposure Response ...........................64 
8.5. 
Pharmacodynamic (PD) Parameters ...............................................................64 
8.6. 
Biomarkers Analyses ......................................................................................64 
8.7. 
Other Variables Analyses ...............................................................................64 
8.7.1. 
Patient Reported Outcomes ............................................................................64 
9. 
CHANGES FROM THE PROTCOL SPECIFIED 
STATISTICAL ANALYSES .......................................................................66 
10. 
REFERENCES .......................................... .. .............................................67 
11. 
APPENDICES ............................................ .... ...........................................68 
11.1. 
Data Derivation Details ....................... ...... .................................................68 
11.1.1. 
Windows Convention for Handling Partial and Missing Dates ......................68 
11.2. 
Interim Analysis Statistical Analysis Plan ......................................................70 
11.3. 
Formula for Wilson Method .. ..... ...............................................................71 
11.4. 
Mock-up Tables and Listings .......................................................................72 
 
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LIST OF TABLES 
Table 15.1.1  
Subject Disposition (All Screened Subjects)  
Table 15.1.2.1  
Demographic and Baseline Characteristics (Full Analysis Set)  
Table 15.1.2.2  
Demographic and Baseline Characteristics (Per-Protocol Analysis Set)  
Table 15.1.2.3  
Demographic and Baseline Characteristics (Safety Analysis Set)  
Table 15.1.3  
Study Drug Exposure (Safety Analysis Set)  
Table 15.1.4.1 
Prior Medications by ATC Class and Preferred Term (Safety Analysis Set) 
Table 15.1.4.2 
Concomitant Medications by ATC Class and Preferred Term (Safety 
Analysis Set) 
Table 15.2.1.1 
Analysis of Progression Free Survival (PFS) (Full Analysis Set) 
Table 15.2.1.2 
Analysis of Progression Free Survival (PFS) (Per Protocol Analysis Set) 
Table 15.2.1.3 
Subgroup Analysis of Progression Free Survival (PFS) (Full Analysis Set) 
Table 15.2.1.4 
Analysis of Progression Free Survival (PFS) for Different HRG Cutoffs (Full 
Analysis Set) 
Table 15.2.2.1 
Analysis of Overall Survival (OS) (Full Analysis Set) 
Table 15.2.2.2 
Analysis of Overall Survival (OS) (Per Protocol Analysis Set) 
Table 15.2.2.3 
Subgroup Analysis of Overall Survival (OS) (Full Analysis Set) 
Table 15.2.2.4 
Analysis of Overall Survival (OS) for Different HRG Cutoffs (Full Analysis 
Set) 
Table 15.2.3.1 
Best Overall Tumor Response and Objective Response Rate (ORR) (Full 
Analysis Set) 
Table 15.2.3.2 
Best Overall Tumor Response and Objective Response Rate (ORR) (Per 
Protocol Analysis Set) 
Table 15.2.4 
Duration of Objective Response/Stable Disease and Time to 
Response/Disease Progression (Full Analysis Set) 
Table 15.2.5 
Summary of Chang  and the Percent Change from Baseline in the Sum of 
Longest Diameters of Target Lesions (Full Analysis Set) 
Table 15.3.1.1  
Overview of Number (%) of Subjects Reporting Treatment-Emergent 
Adverse Events (Safety Analysis Set)  
Table 15.3.1.2  
Number and Percentage of Subjects with Treatment-emergent Adverse 
Events Summarized by Worst CTCAE Grade, System Organ Class, and 
Preferred Term (Safety Analysis Set)  
Table 15.3.1.3  
Number and Percentage of Subjects with Treatment-emergent Serious 
Adverse Events Summarized by Worst CTCAE Grade, System Organ Class, 
and Preferred Term (Safety Analysis Set)  
Table 15.3.1.4  
Number and Percentage of Subjects with Treatment-emergent Adverse 
Events Related to Patritumab/Placebo Summarized by Worst CTCAE Grade, 
System Organ Class, and Preferred Term (Safety Analysis Set)  
Table 15.3.1.5  
Number and Percentage of Subjects with Treatment-emergent Adverse 
Events Related to Cetuximab Summarized by Worst CTCAE Grade, System 
Organ Class, and Preferred Term (Safety Analysis Set)  
Table 15.3.1.6  
Number and Percentage of Subjects with Treatment-emergent Adverse 
Events Related to Cisplatin/Carboplatin Summarized by Worst CTCAE 
Grade, System Organ Class, and Preferred Term (Safety Analysis Set)  
Table 15.3.1.7  
Number and Percentage of Subjects with Treatment-emergent Serious 
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Adverse Events Related to Patritumab/Placebo Summarized by Worst 
CTCAE Grade, System Organ Class, and Preferred Term (Safety Analysis 
Set)  
Table 15.3.1.8  
Number and Percentage of Subjects with Treatment-emergent Serious 
Adverse Events Related to Cetuximab Summarized by Worst CTCAE Grade, 
System Organ Class, and Preferred Term (Safety Analysis Set)  
Table 15.3.1.9  
Number and Percentage of Subjects with Treatment-emergent Serious 
Adverse Events Related to Cisplatin/Carboplatin Summarized by Worst 
CTCAE Grade, System Organ Class, and Preferred Term (Safety Analysis 
Set)  
Table 15.3.1.10 
Number and Percentage of Subjects with Potential Hy’s Law Event by Worst 
CTCAE Grade, System Organ Class, and Preferred Term (Safety Analysis 
Set) 
Table 15.3.4.1  
Summary of Results and Change from Baseline in Laboratory Tests – 
Hematology (Safety Analysis Set)  
Table 15.3.4.2  
Summary of Results and Change from Baseline in Laboratory Tests – 
Chemistry (Safety Analysis Set)  
Table 15.3.4.3  
Shift Table of CTCAE Grade in Labor tory Tests – Hematology (Safety 
Analysis Set) 
Table 15.3.4.4  
Shift Table of CTCAE Grade in Labora ory Tests – Chemistry (Safety 
Analysis Set)  
Table 15.3.4.5 
Number and Percentage of Subjects with Liver Enzymes (ALT, AST) and 
Total Bilirubin (TBL) Elevation (Safety Analysis Set) 
Table 15.3.5  
Summary of Vital Signs and Change from Baseline (Safety Analysis Set)  
Table 15.3.6.1  
Summary of 12-Lead ECG and Change from Baseline (Safety Analysis Set)  
Table 15.3.6.2  
Summary of Subjects M eting Pre-Specified QT and QTcB/QTcF Criteria 
(Safety Analysis Se )  
Table 15.3.7 
Shift Table of ECOG S tus (Safety Analysis Set) 
Table 15.3.8 
Summary of L ft Ventricular Ejection Fraction (LVEF) Value and Change 
from Baseline (Safety Analysis Set) 
Table 15.4.1.1 
Summary of Patritumab Concentration (ug/mL) from Sparse PK Sampling 
(Pharmacokinetics Analysis Set) 
Table 15.4.1.2 
Summary of Patritumab Concentration (ug/mL) from Intensive PK Sampling 
at Cycle 1 (Pharmacokinetic Analysis Set) 
Table 15.4.1.3 
Summary of Cetuximab Concentration (ug/mL) from Intensive PK Sampling 
at Cycle 1 (Pharmacokinetic Analysis Set) 
Table 15.4.1.4 
Summary of Cisplatin Concentration (ug/mL) from Intensive PK Sampling at 
Cycle 1 (Pharmacokinetic Analysis Set) 
Table 15.4.1.5 
Summary of Carboplatin Concentration (ug/mL) from Intensive PK 
Sampling at Cycle 1 (Pharmacokinetic Analysis Set) 
Table 15.4.2.1 
Summary of Patritumab PK Parameters at Cycle 1 (Pharmacokinetic 
Analysis Set) 
Table 15.4.2.2 
Summary of Cetuximab PK Parameters at Cycle 1 (Pharmacokinetic 
Analysis Set) 
Table 15.4.2.3 
Summary of Cisplatin PK Parameters at Cycle 1 (Pharmacokinetic Analysis 
Set) 
Table 15.4.2.4 
Summary of Carboplatin PK Parameters at Cycle 1 (Pharmacokinetic 
Analysis Set) 
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Table 15.4.2.5 
Statistical Analysis of PK Parameters for Cetuximab, Cisplatin, and 
Carboplatin at Cycle 1 (Pharmacokinetic Analysis Set) 
Table 15.5.1.1 
Summary of Actual Results and Change from Baseline in FACT-H&N Total 
Score, FACT-H&N Subscale (HNS) Score, HNS Individual Symptom Score, 
and FACT-H&N Symptom Index (FHNSI) Score (FACT-H&N Analysis Set) 
Table 15.5.1.2 
Statistical Analysis of the Change from Baseline in the FACT-H&N total 
score, the FACT-H&N HNS, HNS individual symptom score, and the 
FACT-H&N FHNSI score (FACT-H&N Analysis Set) 
Table 15.5.1.3 
Summary of Actual Results and Change from Baseline in EQ-5D Index (EQ-
5D Analysis Set) 
Table 15.5.1.4 
Summary of Actual Results and Change from Baseline in VAS Score (EQ-
5D Analysis Set) 
 
 
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LIST OF FIGURES 
Figure 15.1.1 
CONSORT diagram 
Figure 15.2.1.1 
Kaplan-Meier Plot of Progression Free Survival (PFS) by Treatment 
Group (Full Analysis Set) 
Figure 15.2.1.2 
Forest Plot of Progression Free Survival (PFS) for Selected 
Subgroups (Full Analysis Set) 
Figure 15.2.1.3 
Kaplan-Meier Plot of Progression Free Survival (PFS) for Different 
HRG Cutoffs by Treatment Group (Full Analysis Set) 
Figure 15.2.1.4 
Forest Plot of Progression Free Survival (PFS) for Different HRG 
Cutoffs (Full Analysis Set) 
Figure 15.2.2.1 
Kaplan-Meier Plot of Overall Survival (OS) by Treatment Group 
(Full Analysis Set) 
Figure 15.2.2.2 
Forest Plot of Overall Survival (OS) for Selected Subgroups (Full 
Analysis Set) 
Figure 15.2.2.3 
Kaplan-Meier Plot of Overall Survival (OS) for Different HRG 
Cutoffs by Treatment Group (Full Analysis Se ) 
Figure 15.2.2.4 
Forest Plot of Overall Survival (OS) for Different HRG Cutoffs 
(Full Analysis Set) 
Figure 15.2.3.1 
Waterfall Plot of Best (Minimum) Per
nt Change in Sum of Longest 
Diameters from Baseline in T rget Lesions (Full Analysis Set) 
Figure 15.2.4 
Swimmer Plot of Duration of Response (Full Analysis Set) 
Figure 15.4.1.1 
Mean Plasma Concentration of Patritumab by Time from Sparse PK 
Sampling (Pharmacokinetic Analysis Sets) 
Figure 15.4.1.2 
Mean Plasma Concentration of Patritumab by Time from Intensive PK 
Sampling (Pharmacokinetic Analysis Sets) 
Figure 15.4.1.3 
Mean Plasma Con entration of Cetuximab by Time from Intensive PK 
Sampling (Pharmacok netic Analysis Sets) 
Figure 15.4.1.4 
Mean Plasm  Concentration of Cisplatin by Time from Intensive PK 
Sampling (Pharmacokinetic Analysis Sets) 
Figure 15.4.1.5 
Mean Plasm  Concentration of Carboplatin by Time from Intensive PK 
Sampling (Pharmacokinetic Analysis Sets) 
Figure 15.4.2.1 
Boxplot of Patritumab PK Parameters at Cycle 1 (Pharmacokinetic Analysis 
Sets) 
Figure 15.4.2.2 
Boxplot of Cetuximab PK Parameters at Cycle 1 by Treatment 
(Pharmacokinetic Analysis Sets) 
Figure 15.4.2.3 
Boxplot of Cisplatin PK Parameters at Cycle 1 by Treatment 
(Pharmacokinetic Analysis Sets) 
Figure 15.4.2.4 
Boxplot of Carboplatin PK Parameters at Cycle 1 by Treatment 
(Pharmacokinetic Analysis Sets) 
Figure 15.5.1.1 
Plot of Cumulative Distribution Function of Change from Baseline on 
FACT-H&N HNS Score (FACT-H&N Analysis Set) 
Figure 15.6.1 
Heregulin (HRG) Distritubution, Full Analysis Set 
 
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LIST OF DATA LISTINGS 
Listing 16.2.1.1   
Subject Disposition  
Listing 16.2.1.2   
Deaths  
Listing 16.2.2.1   
Inclusion/Exclusion Criteria  
Listing 16.2.2.2  
Informed Consent 
Listing 16.2.2.3   
Protocol Deviation  
Listing 16.2.3   
Subject Inclusion in Analysis Sets  
Listing 16.2.4.1   
Demographic Data  
Listing 16.2.4.2   
Pregnancy Test Results  
Listing 16.2.4.3   
Medical/Surgical History  
Listing 16.2.4.4.1   
Cancer History for SCCHN 
Listing 16.2.4.4.2   
Prior Head and Neck Systemic Cancer Therapy 
Listing 16.2.4.4.3  
Prior Radiation Therapy  
Listing 16.2.4.5   
Prior/Concomitant Medication  
Listing 16.2.4.6   
Non-Drug Treatment/Procedures  
Listing 16.2.5.1.1   
Investigational Drug Patritumab Adminis ration  
Listing 16.2.5.1.2   
Cetuximab, Cisplatin, and Carboplatin Administration  
Listing 16.2.5.1.3  
Patritumab, Cetuximab, and Cisplatin/Carboplatin Exposure  
Listing 16.2.5.2.1  
Patritumab Pharmacokinetic Sample Collection Time and Results  
Listing 16.2.5.2.2  
Cetuximab Pharmacokinetic Sample Collection Time and Results  
Listing 16.2.5.2.3  
Patritumab Pharmacokinetic Sample Collection Time and Results  
Listing 16.2.5.2.4  
Cetuximab Pharmacokinetic Sample Collection Time and Results  
Listing 16.2.6.1.1   
Target Tumor Assessment  
Listing 16.2.6.1.2   
Non-Target Tumor Assessment  
Listing 16.2.6.1.3   
Overall Tumor Ass ssment  
Listing 16.2.6.2 
Progression-Fre  Survival and Overall Survival 
Listing 16.2.6.3 
Subjects with Complete Response (CR), Partial Response (PR), or 
Stable Dis ase (SD) 
Listing 16.2.7.1   
Adv se Event   
Listing 16.2.7.2   
Serious Adverse Events, Including those Leading to Deaths  
Listing 16.2.7.3   
Adverse Events Leading to Study Drug Discontinuation  
Listing 16.2.7.4  
Adverse Event Leading to Study Drug Interruption or Dose Reduction  
Listing 16.2.7.5   
Adverse Events of Interest  
Listing 16.2.8.1.1   
Laboratory Data – Hematology  
Listing 16.2.8.1.2   
Laboratory Data – Chemistry  
Listing 16.2.8.1.3   
Laboratory Data – Urinalysis  
Listing 16.2.8.1.4   
Laboratory Data – Coagulation 
Listing 16.2.8.2.1   
Clinically Significant Laboratory Abnormalities or Abnormalities of 
CTCAE Grade 3/4 Hematology  
Listing 16.2.8.2.2   
Clinically Significant Laboratory Abnormalities or Abnormalities of 
CTCAE Grade 3/4 Chemistry  
Listing 16.2.8.2.3 
Subjects with Liver Enzymes (ALT, AST) and Total Bilirubin (TBL) 
Elevation (Safety Analysis Set) 
Listing 16.2.8.3.1   
Vital Signs  
Listing 16.2.8.3.2   
12 Lead ECG  
Listing 16.2.8.3.3   
Physical Examination 
Listing 16.2.8.3.4  
Eastern Cooperative Oncology Group (ECOG) Score 
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Listing 16.2.8.3.5  
Echocardiogram 
Listing 16.2.8.4.1  
Human Anti-Humanized Antibody (HAHA) 
Listing 16.2.8.4.2  
Tumor Tissue Collection and Biomarker Results  
Listing 16.2.9.1.1 
FACT-H&N Item Scores 
Listing 16.2.9.1.2 
FACT-H&N Total and Subscale Scores 
Listing 16.2.9.2 
EQ-5D Scale Scores 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ABBREVIATION 
DEFINITION 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
AUC0-21d 
Area under curve at last time point 
Cmax 
Maximum observed circulating concentration 
CR 
Complete response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events  
ECG 
Electrocardiograph 
ECOG 
Eastern Cooperative Oncology Group  
EOI 
End of infusion  
EQ-5D-5L 
EuroQoL-5 Dimensions-5 Levels  
EWB 
Emotional well-being  
FACT-H&N 
Functional Assessment of Cancer Therapy-Head and Neck  
FHNSI 
FACT-Head and Neck Symptom Index  
FWB 
Functional well-being 
GFR 
Glomerular filtration rate  
HAHA 
Human antihuman antibody 
HNS 
FACT-Head and Neck Subscale  
HPV 
Human p pilloma virus  
HRG 
Heregulin (product neuregulin-1 gene [nRG1]) 
ILD 
Interstitial Lung Disease  
IV 
Intraven us  
IXRS 
Interactive Web/Voice Response System 
LD 
longest diameters  
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
Multigated acquisition (scan) 
NCI 
National Cancer Institute 
ORR 
Objective response rate  
OS 
Overall survival  
PFS 
Progression-free survival  
PK  
Pharmacokinetic or pharmacokinetics 
PR 
Partial response 
PROs 
Patient reported outcomes  
PWB 
Physical well-being  
QTc (QTcB; QTcF) Heart rate-corrected QT interval (by Bazett’s; by Fridericia’s) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
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ABBREVIATION 
DEFINITION 
SAP 
Statistical analysis plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable disease 
SWB 
Social well-being 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WBC 
White Blood Count 
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1. 
SCOPE 
This Statistical Analysis Plan (SAP) is created based on Protocol U31287-A-U203 
version 4.0, 13 JUN 2016. This version describes in detail the statistical methodology and 
the statistical analyses to be conducted for the above mentioned protocol. The analysis 
plan may change due to unforeseen circumstances. Any deviations to the planned 
statistical analyses specified within the SAP will be justified in writing and presented 
within the clinical study report. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
 
To evaluate PFS in the HRG high expression population from subjects treated 
with patritumab + cetuximab + platinum-based therapy compared to placebo + 
cetuximab + platinum-based therapy 
2.2. 
Secondary Objectives 
 
Evaluate OS 
 
Evaluate objective response rate (ORR) 
 
Refine the cutoff between HRG high and low xpression based on clinical 
data from this study 
 
Assess the population PK of patritumab in subjects with SCCHN 
 
Assess the PK parameters of serum cetuximab and platinum concentrations 
when cetuximab and cisplatin or carboplatin (platinum-based therapy) are 
coadministered with patritumab in  subgroup (n = 30) of subjects 
 
Evaluate the incidence of HAHA formation (anti-patritumab antibodies) 
 
Evaluate the safety and tolerability of the combination of patritumab + 
cetuximab + platinum-based herapy in first-line treatment of subjects with 
SCCHN 
2.3. 
Exploratory Objectives 
 
Duration of response, time to response, time to disease progression, duration 
of SD from subjects treated with patritumab + cetuximab + platinum-based 
therapy compared to those treated on placebo + cetuximab + platinum-based 
therapy 
 
Explore potential exposure-response and possibly other biomarker 
relationships 
 
Evaluate disease specific patient reported outcomes (PROs) using the 
Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) 
which assesses: 
- Physical well-being 
- Functional well-being 
- Social/Family well-being 
- Emotional well-being 
- Head and neck cancer symptoms 
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 Evaluate head and neck cancer symptoms using the FACT-Head and Neck 
Symptom Index (FHNSI), a 10-item instrument comprising items from the 
FACT-H&N 
 Evaluate PROs using the EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) 
questionnaire, which assesses five dimensions: 
- Mobility 
- Self-care 
- Usual activities 
- Pain/discomfort 
- Anxiety/depression  
 
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3. 
STUDY DESIGN 
3.1. 
General Study Design and Plan 
This is a multicenter, randomized, placebo-controlled, double blind Phase 2 study to 
evaluate the PFS and safety in recurrent/metastatic first-line SCCHN in subjects treated 
with patritumab plus cetuximab plus platinum-based therapy compared with subjects 
randomized to the control arm consisting of placebo plus cetuximab plus platinum-based 
therapy.  
Adult subjects with metastatic SCCHN originating from the oral cavity, oropharynx, 
hypopharynx, and larynx with documented disease recurrence following previous 
treatment for non-metastatic disease will be studied. 
Approximately 105 subjects will be randomized 1:1 to the patritumab and the control 
arms stratified by HRG value (high versus low) and HPV status (positive vs negative). 
Approximately 70 HRG-high and approximately 35 HRG-low subjects will be 
randomized. When one HRG stratum is filled with the required sample size, the 
enrollment in that HRG stratum will cease. The initial cut-off for HRG high versus low 
before randomization was set using the median HRG delta Ct value (0.93) of commercial 
tissue samples and was increased based on further samples to 1.50 on 29JUL2016. See 
Figure 3.1.1 for a schematic of the study d sign  
Figure 3.1.1:  Phase 2 Study Design 
 
There will be two treatment arms: 
1. Patritumab + cetuximab + platinum-based therapy with HRG high and HRG  
low subjects 
2. Placebo + cetuximab + platinum-based therapy with HRG high and HRG low subjects 
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Figure 3.1.2  illustrates the order and timing of the treatments involved. 
 
Figure 3.1.2: Order and Timing of Treatments 
 
 
Patritumab initial loading dose is 18 mg/kg IV (or placebo) over 60 minutes followed in 
cycle 2 and beyond with a maintenance dose of 9 mg/kg IV over 60 minutes (± 10 
minutes) every three weeks. Infusion time can be extended to a maximum of 120 minutes 
for subjects unable to tolerate the 60 minute infusion. Cetuximab initial dose at 400 
mg/m2 IV is given as a 2-hour infusion  followed by 250 mg/m2 over 60 minutes weekly.  
One hour after the end of the cetuximab administration (on the weeks when cetuximab 
and platinum therapy are coadministered) infuse with either: 
 Cisplatin at 100 mg/m2 IV infused over 1 hour, every three weeks up to a 
maximum of 6 cycles  Pretreatment hydration with 2 liters of fluid prior to a 
cisplatin infusion is recommended and should adhere to institutional standards. 
Adequate hydration and urinary output must be maintained during the following 24 
hours. Other pretreatments such as anti-emetic prophylaxis and posttreatments 
such as hydration are up to the discretion of the Investigator. This can be given in a 
separate infusion during patritumab and cetuximab infusion; or 
 Carboplatin, IV bolus over 30-60 minutes, every 3 weeks for a maximum of 6 
cycles. AUC 5 is the target. The carboplatin dose will be calculated using the 
Calvert formula: Carboplatin Dose (mg) = 5 x (glomerular filtration rate [GFR] + 
25). Estimated serum creatinine clearance (mL/min) calculated using the modified 
Cockcroft-Gault equation also be used as an estimate for GFR. The carboplatin 
dose is required to be re-calculated for every dosing based on the current GFR (or 
creatinine clearance as an estimate of GFR as per the protocol). 
Pre- and post-treatments are up to the discretion of the investigator. 
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For the purpose of collecting survival data, the duration of the study will be until all 
subjects have died or a minimum of 13 months after the last subject is randomized 
whichever comes first, approximately 22 months for PFS and 25 months for OS. 
The screening period is up to 14 days. Each cycle of treatment will be 21 days. There is 
no limit to how many cycles for patritumab and cetuximab treatment. Treatment will 
continue without interruption in subjects with CR, partial response PR, or SD. However, 
platinum treatment (cisplatin or carboplatin) will be given up to a maximum of 6 cycles. 
Subject participation is expected to be approximately 20 months. 
Subjects who demonstrate benefit from therapy may continue in the extension phase 
(Section 6.5) to receive treatment until progressive disease (PD), toxicity, withdrawal of 
consent, or starting another treatment for cancer therapy. 
The study evaluation schedule is provided in Table 3.1.1 and Table 3.1.2 
 
 
 
 
 
 
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  Table 3.1.1: 
Schedule of Events 
Assessment 
Tissue 
screen 
Screen 
Random-
ization 
Cycle 1 (Weeks 1-3) 
Cycles 
2 & 3 
Cycle 4 & 
all 
Subsequent 
Cycles 
End of 
Cycle 6 
& Every 
4 Cycles 
Every 
6 
weeks 
End-of-
Study 
Treatment 
Visit 
40 Days 
After 
Last 
Dosea 
Day 1 
Day 2 Day 3 Day 8 Day 15 
Day 1 
Day 1 
 
 
 
 
Predose Dosing EOI 
Visit Window (Days) 
 
-14 unless 
otherwise 
indicated 
 
 
 
 
 
 
 
 
 
 
 
 
21 days 
after last 
dose a 
 
Informed consent for 
tumor tissue 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent (s) b 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
(including smoking 
history) & 
demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam  
 
X 
 
X 
 
 
 
 
X 
X 
X* 
X* 
 
 
X 
 
Vital signs  
 
X 
 
X 
 
X 
 
 
X 
X 
X* 
X* 
 
 
X 
 
Height & weight c 
 
X 
 
X d 
 
 
 
 
 
 
X*d 
X*d 
 
 
Xd 
 
ECOG 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
X 
 
Echo or MUGA e 
 
X 
 
 
 
 
 
 
 
 
X e 
X e 
 
 
X 
 
ECG (12-lead) e 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Con Meds 
 
X 
 
X 
 
X 
 
 
X 
X 
X* 
X* 
 
 
X 
 
Adverse Events 
X f 
X 
 
X 
 
X 
 
 
X 
X 
X* 
X* 
 
 
X 
X g 
PRO assessments h 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
 
CBC differential & 
platelets i 
 
X 
 
X d 
 
 
 
 
X d 
X d 
X* d 
X* d 
 
 
X d 
 
Serum chemistries i  
 
X 
 
X d 
 
 
 
 
X d 
X d 
X* d 
X* d 
 
 
X d 
 
GFR or estimated 
serum creatinine 
clearance j 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
Coagulation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
IxRS 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intense PK k 
 
 
 
X d 
 
X 
X 
X 
X 
X 
X† 
 
 
 
 
 
Sparse PK (all) l 
 
 
 
X d 
 
X 
 
 
 
 
X 
 
 
 
X 
 
HAHA sample l 
 
 
 
X d 
 
 
 
 
 
 
X 
 
 
 
X 
 
Pregnancy test m 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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Assessment 
Tissue 
screen 
Screen 
Random-
ization 
Cycle 1 (Weeks 1-3) 
Cycles 
2 & 3 
Cycle 4 & 
all 
Subsequent 
Cycles 
End of 
Cycle 6 
& Every 
4 Cycles 
Every 
6 
weeks 
End-of-
Study 
Treatment 
Visit 
40 Days 
After 
Last 
Dosea 
Day 1 
Day 2 Day 3 Day 8 Day 15 
Day 1 
Day 1 
 
 
 
 
Predose Dosing EOI 
Patritumab Adm n 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
Cetuximab Adm o 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
Platinum Adm p 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
PGx sample q 
 
 
 
X d 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessments r 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X s 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X t 
Additional biomarker 
blood samples u 
 
 
 
X u 
 
 
 
 
 
 
X u 
 
X u 
 
X u 
X u 
a 
Last dose of any study drug administered. 
b 
Informed consent for main study (mandatory) and pharmacogenomics (optional). 
c 
Height measured only at Screening. 
d 
These assessments can be performed within 3 days prior to visit. 
e 
Echocardiograms/MUGA scans will be performed at Screening, Cycle 3,  every third subsequent cycle, and End-of-Study Visit. Additional echocardiograms/MUGA 
scans and electrocardiograms may be performed at the discretion of th  inve tigator. The same test (echocardiogram or MUGA) must be used for a subject throughout the 
study. 
f 
Collect SAEs only related to the biopsy procedure. 
g 
At 40 days after the last dose of study drug, a telephone call will e pl ced to the subject to record adverse events. 
h 
PRO assessments will be administered before any study-rela ed procedures are performed. 
i 
Results must be available prior to dosing. 
j 
At Screening, either GFR or the estimated serum creatinin  clear nce (mL/min) as an estimate of GFR will be calculated. The estimated serum creatinine clearance rate 
(CrCl; mL/min) will be calculated using the modified Cockcroft-Gault equation (Appendix 17.1). The estimated GFR will also be calculated before each cisplatin or 
carboplatin administration. This will be performed only until completion of chemotherapy.  
k 
Intensive serum PK in a subgroup of 30 subjects samples will be collected. See Error! Reference source not found. in the protocol for detailed information on 
sampling times. 
l 
See Error! Reference source not found. in the protocol for detailed information on sampling times. 
m 
Pregnancy test must be confirmed negative before dosing. Additional pregnancy testing may be done at the discretion of the Investigator and/or if required by local 
regulations for women of child-bearing potential. 
n 
Patritumab administered initially at 18 mg/kg and thereafter 9 mg/kg every 3 weeks as a continuous intravenous infusion over 60 minutes ( ±10 minutes). Infusion times 
can be extended to a maximum of 120 minutes for subjects unable to tolerate the 60-minute infusion. 
o 
Cetuximab infusions administered initially at 400 mg/m2 IV over 2 hours and 250 mg/m2 over 1 hour weekly. Cetuximab is administered 60 minutes after patritumab 
administration. Cetuximab is given on Days 1, 8, and 15. 
p 
Cisplatin infusions administered at 100 mg/m2 IV over 1 hour and every 3 weeks up to a maximum of 6 cycles. For pre- and post-treatment hydration see Section Error! 
Reference source not found. in the protocol and according to institutional standards. Creatinine clearance required prior to cisplatin administration. Cisplatin 
administered 1 hour after cetuximab administration. If carboplatin is selected instead of cisplatin, administer carboplatin at AUC of 5 over 30-60 minutes every 3 weeks 
for a maximum of 6 cycles. See Section Error! Reference source not found. in the protocol for carboplatin. 
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q 
Genetic sampling is optional. 
r 
Tumor measurements will be assessed per RECIST Version 1.1. Baseline scans to be performed as part of eligibility during Screening. Existing radiographic scans can be 
used for the baseline evaluation if the scans were performed within 4 weeks prior to randomization. 
s 
Tumor assessments are to be performed every 6 weeks to Week 24 (+/- 3 days), then every 12 weeks (+/- 7 days) thereafter. 
t 
After discontinuation from study treatment, follow-up information for survival will be obtained per telephone approximately every 3 months for a minimum of 13 months. 
u 
Additional biomarker samples: 
 
Collect blood sample for cfDNA predose Cycle 1 Day 1, predose Cycle 2 Day 1, End of Cycle 6,  predose every 4 Cycles, at progression (end of study treatment), and 40 
days after last dose of study drug administered.  
 
Collect blood samples for exosome at: predose Cycle 1 Day 1, predose Cycle 2 Day 1, and End of Cycle 6. Refer to the laboratory manual for instructions on collection 
and management of samples. 
* 
Can be collected on Days 8 and 15 in all subsequent cycles at the discretion of the Investigator. 
† 
Corresponds to Cycle 1, Day 21 (504 hrs)—see Error! Reference source not found. in the protoc l.  
 
 
 
 
 
 
 
  
                  
 
 
 
 
 
 
 
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Table 3.1.2:    Schedule of Events for Extension Phase 
 
Additional cycles 
Every 3 months 
End of 
Treatment 
40 days after 
last dosea 
Predose 
Dosing 
 
 
 
Visit Window (Days) 
 
 
 
 
 
Physical Exam 
X 
 
 
X 
 
Vital Signs 
X 
 
 
X 
 
Adverse Events 
X 
 
 
 
X 
CBC diff and platelets b 
X b 
 
 
X b 
 
Serum chemistries b 
X b 
 
 
X b 
 
HAHA and PK sample c 
 
 
X 
 
 
Patritumab Adm d 
 
X 
 
 
 
Cetuximab Adm e 
 
X 
 
 
 
Additional  biomarker blood samples 
 
 
X 
X 
X 
a 
Last dose of any study drug administered. 
b 
CBC and chemistries must be performed within 3 days of dosing  
c 
For subjects with positive HAHA at the End of Study Trea ment visit, dditional serum HAHA samples should be collected every 3 months up to 1 year from the last dose 
of study drug or if the subject starts another ther py for canc r, or withdraws consent from the study, whichever occurs first. 
d 
Patritumab administered at 9 mg/kg every 3 weeks as  continuous intravenous infusion over 60 minutes (±10 minutes). Infusion times can be extended to a maximum of 
120 minutes for subjects unable to tolerate the 60 minute nfusion. 
e 
Cetuximab is infused at 250 mg/m2 over 1 hour weekly. Cetuximab can be administered directly after patritumab administration. 
 
 
 
 
 
 
 
 
 
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3.2. 
Study Population 
Adult subjects with metastatic SCCHN originating from the oral cavity, oropharynx, 
hypopharynx, and larynx with documented disease recurrence following previous 
treatment for non-metastatic disease will be enrolled. A subject is considered enrolled in 
the study upon the Investigator or designee obtaining written informed consent from the 
subject, and upon determination that all inclusion and exclusion criteria have been 
satisfied. 
3.3. 
Randomization and Blinding 
3.3.1. 
Randomization 
Approximately 105 subjects who have an HRG expression value and HPV status (+/-) 
will be assigned randomly in a blinded manner by the Interactive Web/Voice Response 
System (IXRS) to the patritumab or the control arms in a 2 1 stratification (approximately 
70 HRG-high and approximately 35 HRG-low subjects)  
The IXRS will manage the number of HRG-high and HRG-low patients randomized.   
Once the maximum number of HRG-low subjects has been randomized, the IXRS will 
not allow enrollment of additional HRG-low subjects. To ensure balance between 
treatment groups, subjects will additionally b  stratified according to HPV status 
(positive, negative).  
Randomization to treatment groups will be achieved using IXRS. The time between 
randomization and the initiation of treatment should be as short as possible and no more 
than 3 business days. 
3.3.2. 
Blinding 
This study is randomized, placebo-controlled, double blinded study. The treatment 
assignments will be blinded to the subjects, the investigators, site staff, and all persons 
involved in reviewing the clinical data, including CRO personnel in clinical and trial 
management and Sponsor personnel, with the exception of the Data Monitoring 
Committee, who will review the unblinded clinical data on an ongoing basis. 
3.3.2.1. 
Unblinding at Primary Analysis 
At the point of primary analysis, as defined in Section 7 of this SAP, the treatment 
assignment for all subjects randomized will only be unblinded to CRO and sponsor 
statisticians and programmers directly involved in performing the analyses after data are 
reconciled and cleaned and a snapshot of the clean database is created. To minimize 
potential bias, subjects and investigators will not be informed about individual treatment 
assignment until study closure. Any datasets containing potentially unblinded information 
(i.e., patritumab PK and HAHA) will have their access restricted. The study statistician 
will maintain a list of the individuals who have access to individual treatment 
assignments and/or data that potentially unblinds the study. This list will include the date 
and level of unblinding and rationale for unblinding. 
 
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3.3.2.2. 
Unblinding at Study Closure 
For the purpose of database lock and generation of the clinical study report (CSR), the 
study will be considered closed when OS data will be considered mature. At study 
closure, all subjects will be unblinded for final analysis after the final database is locked.  
Any subject remaining on study treatment and appears to continue to benefit (ie, SD or 
better) from treatment may continue to receive study treatment.  
3.3.2.3. 
Emergency Unblinding 
In the case of a rare emergency where, in the opinion of the Investigator, discontinuation 
of study drug is not sufficient and study treatment must be unblinded to evaluate further 
course of medical treatment. The investigator is encouraged to contact the CRO medical 
monitor to discuss their rationale for unblinding. However, to prevent delays to the 
investigator or medical personnel responding to a potentially emergent situation, 
unblinding of the study treatment will not be dependent pon the investigator receiving 
approval from the CRO medical monitor. The method for determining a subject's 
treatment assignment once a subject is randomized in the study is through the IxRS. The 
investigator and one designated subinvestigator will have access to perform emergency 
unblinding in the IxRS. The treatment assignment of the selected subject randomized at 
their site will be revealed to the investigator performing the IxRS call upon completion of 
the emergency unblinding call. The investigat r must contact CRO medical monitor by 
telephone with an explanation of the need for opening the treatment assignment code 
within 24 hours of opening the code. A detailed procedure is described in the protocol. 
3.4. 
Study Assessments 
The table in Section 3.1, above, presen s the visit schedule and procedures of the study to 
be conducted at each visit. 
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4. 
SAMPLE SIZE DETERMINATION 
The primary efficacy endpoint is PFS. The sample size for this study is based on the 
number of required PFS events in the HRG-high stratum. For PFS, a clinically 
meaningful improvement is defined as 79% increase from median PFS of 4.2 months in 
the control arm to median PFS of 7.5 months in the patritumab arm (that is a HR of 0.56). 
A total of 70 HRG-high subjects will be randomized to observe 53 PFS events in the 
HRG high stratum assuming a one-sided alpha of 0.10, 80% power, and a 1:1 
randomization ratio between 2 arms, a 12-month enrollment and 10-month follow-up, 
and 10% dropouts. 
Under 2:1 (HRG high vs. low) stratification, a total of approximately 105 subjects (70 
HRG high subjects and 35 HRG low subjects) will be randomized in both strata to 
observe at least 75 PFS events. The sample size from bo h strata combined will provide 
approximately 81% power to detect a HR=0.56 in PFS assuming one-sided alpha of 0.05 
and other same assumptions above if HRG high stratum does not show statistical 
significance in PFS. 
The sample size computation is performed using the test based on Survival Superiority 
Trials: Two Sample Test – Logrank Test: Given Accrual Duration and Study Duration in 
the EAST software (version 5.3, Cytel Inc.). 
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5. 
STUDY VARIABLES 
5.1. 
Efficacy Variables 
Efficacy variables include PFS, OS, ORR (CR and PR), duration of response, time to 
response, time to disease progression, and duration of SD. 
Tumor response assessments, including subjects who discontinued from treatment, will 
be performed every 6 weeks (± 3 days) for the first 24 weeks independent of treatment 
cycle until disease progression, death, start of new anticancer therapy, withdrawal of 
subject consent, lost to follow-up, or study closure, whichever occurs first. After 24 
weeks, tumor assessments will be performed every 12 weeks (± 7 days). 
5.1.1. 
Primary Efficacy Variable 
The primary efficacy variable is PFS. PFS is defined as the time from the date of 
randomization to the earlier of the dates of the first objective documentation of 
radiographic disease progression (per RECIST v1.1 as assessed by investigator) or death 
due to any cause. Progressive Disease is defined as ≥ 20% increase in the sum of 
diameters of target lesions; taking as reference the mallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions s also considered progression). 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“clinical progression.” Every effort sho ld be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of 
an objective response: it is a reason for stopping study therapy. The objective response 
status of such subjects is to be determined by evaluation of target and non-target disease. 
If a radiographic tumor assessment has not been performed within 4 weeks of the time of 
clinical progression, then another radiographic assessment should be performed without 
waiting for the next regularly scheduled scan. 
For equivocal findings of progression (ie, very small and uncertain new lesions, cystic 
changes, or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
The rules for censored cases are defined as follows: 
1.  Subjects who are alive with no objective documentation of radiographic disease 
progression by the data cut-off date for the PFS analyses will be censored at the date 
of the last post-baseline evaluable tumor assessment. The evaluable tumor assessment 
is defined as the overall response for tumor assessment being not “Inevaluable” 
recorded on the Case Report Form (CRF) page “overall tumor assessment”. If there is 
no post-baseline evaluable tumor assessment, the subject will be censored at the date 
of randomization. 
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2.  Subjects who start other anti-cancer therapy including surgical or radiologic 
intervention given with curative intent prior to progression or death will be censored 
at the date of the last post-baseline evaluable tumor assessment prior to starting other 
anti-cancer therapy. If there is no post-baseline evaluable tumor assessment prior to 
starting other anti-cancer therapy, the subject will be censored at the date of 
randomization. 
3. Subjects who progress or die after ≥2 consecutive missed tumor assessment visits will 
be censored at the date of the last evaluable tumor assessment prior to progression or 
death. In this study, progression or death after ≥2 consecutive missed tumor 
assessment visits is defined as progression or death that occurs more than 13 weeks 
(two tumor assessment visits plus 1 week visit window) since the last post-baseline 
evaluable tumor assessment. If there is no post-baseline evaluable tumor assessment 
prior to the tumor assessment of progressive disease or death and progression or death 
occurs more than 13 weeks since the date of randomization, the subject will be 
censored at the date of randomization;  
4. Subjects without baseline tumor assessment will be censored at the date of 
randomization. 
5.1.2. 
Secondary Efficacy Variables 
Secondary efficacy variables include OS and ORR (CR and PR).  
5.1.2.1. 
Overall Survival (OS) 
OS is defined as the time from the date of randomization to death due to any cause. 
Subjects who are alive at the time of data cut off for OS analysis will be censored at the 
last contact date at which the subject is known to be alive.  
Survival status data will be obtained from deaths reported in the CRFs and Survival 
follow-up communications every 3 months after a subject discontinues from study 
treatment. 
The last contact date is defined as the last date the subject was known to be alive at the 
analysis cut-off. The date will be the latest date among the following: 
 Last non-missing assessment/onset date captured under the following eCRF pages 
(or if a date of assessment/onset is not available the “date of visit” for the eCRF 
page can be used): adverse events, vital signs, physical examination, ECOG PS, 
ECG, Echocardiogram or MUGA scan, safety laboratory test, tumor assessment, 
patient-reported outcomes assessment, hospitalization and also assessment date in 
third-party data such as PK, HAHA etc.  
 Last dosing date of study medication, last date of concomitant medications, and 
last date of non-drug treatments/procedures.  
 Start date of subsequent anti-cancer therapy administered after study treatment 
discontinuation.   
 Date of Last Contact collected on the survival follow up page of the eCRF. 
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 Date of Last Contact collected on the final subject status (or end of study status) 
page of the eCRF. 
5.1.2.2. 
Object Response Rate (ORR) 
ORR is defined as the proportion of subjects with the best overall response of CR or PR. 
A confirmation of CR/PR is not required for this study as per RECIST Version 1.1. 
The best overall response is defined as the best response (in the order of CR, PR, SD, and 
PD) among all overall responses recorded from the start of treatment until the subject is 
withdrawn from the study.The best overall response of PD corresponds to disease 
progression (assessment based upon tumor measurements and recorded on the CRF page 
“overall tumor assessment”) for the first valid post-treatment tumor assessment. If there 
is no post-treatment tumor assessment, the best overall response will be assigned as 
“Inevaluable”. In the case of a best overall response of SD, measurements must have met 
the SD criteria at least once after study entry at a minimum time interval from baseline. A 
best overall response of SD must be assessed a minimum of 39 days (6 weeks – 3 day 
visit window) after the date of randomization. If this minimum requirement is not met, 
the best overall response will be determined starting with the next tumor assessment. If 
there is no next tumor assessment, the best overall response will be assigned as 
“Inevaluable”.   
5.1.3. 
Exploratory Efficacy Variables 
Duration of response, time to response, time to disease progression and duration of SD 
will be exploratory efficacy variables examined in this study. 
5.1.3.1. 
Duration of Response 
Duration of response is defined as the time from the date of the first documentation of 
objective response (CR or PR) to the date of the first documentation of progressive 
disease (disease progression as assessed based upon tumor measurements and recorded 
on the CRF page “overall tumor assessment”). If a subject is discontinued or is lost to 
follow-up with no documentation of progressive disease, duration of response is defined 
as the time from the date of the first documentation of objective response to the date of 
the last evaluable tumor assessment as a censored value. The rules for censored cases are 
defined as follows: 
Subjects who progress after ≥2 consecutive missed tumor assessment visits will be 
censored at the date of the last evaluable tumor assessment prior to the tumor assessment 
of progressive disease. In this study, progression after ≥2 consecutive missed tumor 
assessment visits is defined as progression that occurs more than 13 weeks (two tumor 
assessment visits plus 1 week visit window) since the last post-baseline evaluable tumor 
assessment. Subjects who start other anti-cancer therapy prior to progression will be 
censored at the date of the last post-baseline evaluable tumor assessment prior to starting 
other anti-cancer therapy.  
Duration of response will be measured for responding subjects (PR or CR) only. 
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5.1.3.2. 
Time to Response 
Time to response is defined as the time from the date of randomization to the date of the 
first documentation of objective response (CR or PR). Time to response will be measured 
for responding subjects (PR or CR) only. 
5.1.3.3. 
Time to Disease Progression (TTP) 
Time to progression is defined as the time from the randomization date to the date of first 
objective documentation of radiographic disease progression (per RECIST v1.1 as 
assessed by investigator). Objective documentation of disease progression is based upon 
“Overall Response” recorded as “Progressive Disease (PD)” on the CRF page: “overall 
tumor assessment”. The rules for censored cases of TTP and duration of response are 
similar to the censoring of PFS, except that subjects who die before disease progression is 
document are censored for the former. 
5.1.3.4. 
Duration of Stable Disease (SD) 
Duration of stable disease is defined for subjects whose best response is SD as the time 
from the date of randomization to the date of the first documentation of progressive 
disease (disease progression as assessed based upon tumor measurements and recorded 
on the CRF page “overall tumor assessment”). Censoring rules are the same as described 
above for duration of response. 
5.2. 
Safety Variables 
5.2.1. 
Adverse Events 
The following safety variables will be assessed in this study according to the Schedule of 
Events (Table 3.1.1 and Table 3 1.2) in Section 3.1. 
 A Treatment-eme g nt adverse event (TEAE) is defined as an Adverse Event 
(AE) that emerges during treatment, having been absent at pretreatment, or 
reemerges during treatment, having been present at baseline but stopped prior 
to treatment, or worsens in severity since treatment relative to the pretreatment 
state, when the AE is continuous. Adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA, Version XX.X), and 
graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03.  
 AEs of Special Interest 
 Interstitial Lung Disease (ILD) 
      ILD is defined as an acute onset of new or progressive pulmonary symptoms, 
such as dyspnea, cough or fever. 
 Combined Elevations of Aminotransferases and Bilirubin 
Hepatic events, both serious and nonserious, presenting with combined 
abnormalities meeting criteria for a potential “Hy’s law” case [i.e., Alanine 
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aminotransferase (ALT) or Aspartate aminotransferase (AST) ≥ 3 x ULN, 
with simultaneous total bilirubin ≥ 2 x ULN]. 
5.2.2. 
Clinical Laboratory Evaluations 
Safety laboratory assessments will include hematology, serum chemistry, coagulation, 
and urinalysis. 
 Coagulation (only at Screening): prothrombin time, international normalized 
ratio, and partial thromboplastin time 
 Hematology: CBC including hemoglobin, hematocrit, white blood cell count 
(WBC) with 5 part differential (including absolute neutrophil count), red 
blood cell, and platelet count 
 Serum chemistry: bicarbonate, calcium, phosphorus, magnesium, albumin, 
glucose, serum creatinine, uric acid, total protein, urea, AST, ALT, lactic 
dehydrogenase, alkaline phosphatase, total and direct bilirubin, sodium, 
potassium, and chloride 
 Routine urinalysis: dipstick and microscopy (if indicated), including protein, 
specific gravity, glucose, and blood  
 Serum or urine β-HCG pregnancy t st 
At Screening, creatinine clearance (mL min) or GFR will be calculated. This will also be 
done before each cisplatin or carboplatin administration. 
5.2.3. 
Vital Signs 
Vital sign measurements include blood p essure, heart rate, temperature, height, and 
weight. 
5.2.4. 
ECG 
A 12-lead ECG will be performed within 14 days prior to Screening, at the End of Study 
Treatment visit, and during the study at the discretion of the Investigator. 
5.2.5. 
Physical Examinations 
Physical examinations will evaluate the following body systems/organs: respiratory, 
cardiovascular, gastrointestinal, musculoskeletal, genitourinary/reproductive (optional), 
psychiatric (optional), hematological, neurological, immunological, head, eyes, ears, nose 
and throat, and other. Abnormal physical examination findings that are new or changed 
will be reported as AEs. 
5.2.6. 
Other Safety Variables 
An echocardiogram or multigated acquisition (MUGA) scan will be performed at 
screening, and at End-of-Study Treatment visit and during the study at the discretion of 
the Investigator.   
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The presence of anti-patritumab neutralizing antibody in serum will be assessed. Blood 
samples will be taken on Day 1 of Cycle 1 (preinfusion), Cycle 2 (preinfusion), Cycle 3 
(preinfusion), and at End-of-Study Treatment visit. For subjects with positive anti- 
patritumab neutralizing antibody on the serum sample drawn at the end of study 
treatment visit, additional serum samples should be obtained for antibodies, until the 
antibody level returns to baseline (or becomes negative) or up to 1 year from the last dose 
of study drug or if the subject starts another therapy for cancer, whichever occurs first.  
5.3. 
Pharmacokinetic Variables 
5.3.1. 
Concentration Data 
Serum concentrations for patritumab will be collected at Cycles 1- 3 and at End of Study 
Treatment (Table 8.1 of the Protocol).  
For a subset of 30 subjects, a blood sample for PK analyses of patritumab, cetuximab, 
and platinum concentrations will be obtained at the time points, relative to the start of 
patritumab infusion at Cycle 1 (Table 8.2 of the Protocol)  This will be an intense 
pharmacokinetic (PK) assessment. 
5.3.2. 
Pharmacokinetic (PK) Parameters 
PK parameters (AUC0-21d and Cmax) will be calculated from the individual 
concentrations of patritumab, cetuximab, cisplatin and carboplatin using non-
compartmental methods. PK parameters will be derived for the intensive PK sampling 
(i.e. Cycle 1) for patritumab, cetuximab  cisplatin and carboplatin. 
5.4. 
Pharmacodynamic (PD) Variables 
Not Applicable. 
5.5. 
Biomarkers 
A predictive biomarker will be analyzed with the intent of identifying those subjects who 
might derive clinical benefit from treatment with patritumab. Heregulin is the candidate 
biomarker prospectively selected as the single predictive biomarker. Heregulin messenger 
RNA will be measured in tumor samples using a quantitative reverse transcription 
polymerase chain reaction assay. 
HPV status or p16 will be evaluated in all tumor tissue in this study. 
Further exploratory tissue, soluble, or genomic biomarkers in subject tissue and blood 
samples (possibly including circulating cell-free DNA and exosomes) may be analyzed 
based on emerging scientific knowledge to better understand the target disease and also 
the effects of study treatment. 
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5.6. 
Other Variables 
5.6.1. 
Eastern Cooperative Oncology Group Performance Status 
The Eastern Cooperative Oncology Group (ECOG) performance status will be 
determined at Screening, and then at each scheduled visit throughout the study.  
5.6.2. 
Patient Reported Outcomes 
Patient-reported outcomes will be used to evaluate study treatment in subjects treated 
with patritumab + cetuximab + platinum-based therapy compared to placebo + cetuximab 
+ platinum-based therapy. 
Functional Assessment of Cancer Therapy—Head and Neck (FACT-H&N) 
Instrument 
The FACT-H&N contains 4 general subscales (total 27 items) measuring physical well-
being (PWB), functional well-being (FWB), social well-being (SWB), emotional well-
being (EWB), and a Head and Neck Cancer symptom-sp cific subscale – the 12-item 
Head and Neck Additional Concerns Subscale (HNS).  Each of the 39 FACT- H&N 
items is rated on 5-point scales, ranging from 0=not at all to 4=very much, where higher 
scores represent more favorable patient-reported outcomes.   
Combining the 10 symptom-related items out of the 39 FACT-H&N items – “I have a 
lack of energy” (PWB item 1), “I have nausea” (PWB item 2), “I have pain” (PWB item 
4), “I worry that my condition will get worse” (EWB item 6), “I am content with the 
quality of my life right now” (FWB item 7), “I have trouble breathing” (Additional 
Concerns item 3), “I can swallow naturally and easily” (Additional Concerns item 7), “I 
am able to communicate with others” (Additional Concerns item 10), “I can eat solid 
foods” (Additional Concerns item 11), and “I have pain in my mouth, throat or neck” 
(Additional Concerns item 12) - yields a 10-item FACT-Head and Neck Symptom Index 
(FHNSI). 
Specifically, 7 specific summary scores will be evaluated, 
 PWB score  
 FWB score 
 SWB score 
 EWB score 
 HNS score 
 FHNSI score 
 FACT-H&N total score     
The FACT-H&N Total Score ranges from 0-156. The PWB score, SWB score and EWB 
score range from 0 to 28. The EWB score ranges from 0 to 24. The HNS score and the 
FHNSI score ranges from 0 to 48. The FACT-H&N total score, PWB score, FWB score, 
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SWB score, EWB score, HNS score and FHNSI score will be analyzed as exploratory 
efficacy parameters. 
Use following algorithm to determine the individual subscale scores: 
 Physical well-being (PWB): PWB score = Sum (GP1-GP7) x 7/number of 
nonmissing items. If the number of missing items (GP1-GP7) is greater than 
3, then set PWB score = missing. 
 Social well-being (SWB): SWB score = Sum (GS1-GS7) x 7/number of 
nonmissing items. If the number of missing items (GS1-GS7) is greater than 
3, then set SWB score = missing. 
 Emotional well-being (EWB): EWB score = Sum (GE1-GE6) x 6/number of 
nonmissing items. If the number of missing items (GE1-GE6) is greater than 
3, then set EWB score = missing. 
 Functional well-being (FWB): FWB score = Sum (GF1-GF7) x 7/number of 
nonmissing items. If the number of missing items (GF1-GF7) is greater than 
3, then set FWB score = missing. 
 Additional Concern (HNS): HCS score = Sum (H&N1-H&N12) x 12/number 
of nonmissing items. If the number of missing above items is greater than 6, 
then set HCS score = missing. 
 Additional Concern (HNS): HCS score = Sum (H&N1-H&N12) x 12/number 
of nonmissing items. If the number of missing above items is greater than 6, 
then set HCS score = missing. 
 FHNSI: FHNSI score = Sum of 10 symptom-related items x 10/number of 
nonmissing items  If the number of missing above items is greater than 5, then 
set FHNSI score = missing. 
 FACT-H&N total score: FACT-H&N score = Sum (PWB, SWB, EWB, GFB, 
HCS). If any of the above items is missing, then set FACT-H&N score = 
missing. 
EuroQoL-5 Dimensions-5 Levels Instrument 
The EQ-5D-5L is a preference based measure of health status that is now widely used in 
clinical trials, observational studies, and other health surveys. 
The EQ-5D-5L consists of 2 pages – the EQ-5D-5L descriptive system and the EuroQoL 
Visual Analogue scale (EQ VAS). The descriptive system comprises the following 5 
domains: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each 
domain has 5 levels: no problems (1), slight problems (2), moderate problems (3), severe 
problems (4), and extreme problems (5). The respondent is asked to indicate his/her 
health state by ticking (or placing a cross) in the box with the most appropriate statement 
in each of the 5 domains. This decision results in a 1-digit number expressing the level 
selected for that domain. The digits for 5 domains can be combined in a 5-digit number 
or profile describing the respondent’s health state.  
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As index-based values have not been evaluated for the EQ-5D-5L at this time, crosswalk 
value sets developed based on the EQ-5D-3L index-based values will be applied. The 
crosswalk value set for the United Kingdom will be used for analyses overall and for all 
regions. The value set provides an index score for each health state and can be accessed 
at: 
(http://www.euroqol.org/fileadmin/user_upload/Documenten/Excel/Crosswalk_5L/EQ-5
D-5L_Crosswalk_Value_Sets.xls). 
The EQ VAS records the respondent’s self-rated health on a 20 cm vertical, visual 
analogue scale with endpoints labeled ‘the best health you can imagine’ and ‘the worst 
health you can imagine’. This information is used as a quantitative measure of health as 
judged by the individual respondents. The instructions for the EQ VAS asks respondents 
to ‘mark an X on the scale to indicate how your health is TODAY’ and then to ‘write the 
number you marked on the scale in the box below. 
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6. 
ANALYSIS SETS 
6.1. 
Analysis Sets Definitions 
6.1.1. 
Full Analysis Set 
The full analysis set (FAS) will be based on the intent-to-treat principle and will comprise 
all subjects randomized into the study. Subjects will be analyzed as randomized. 
6.1.2. 
Safety Analysis Set 
The safety analysis set includes all subjects who received any amount of study 
medication. Subjects will be analyzed according to actual treatment received. 
6.1.3. 
Per-Protocol Analysis Set 
The per-protocol analysis set will include all subjects in the FAS who have completed at 
least 1 cycle of treatment, and who were sufficiently compliant with the protocol and 
without major protocol violation. Full criteria for defining sufficient compliance will be 
finalized and documented prior to database unblinding. 
6.1.4. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all sub ects who have received at least 1 dose of study 
drugs and have evaluable patritumab or cetuximab concentrations. 
6.1.5. 
Patient Reported Outcome Analysis Set 
There will be 2 PRO Analysis Sets:  
 FACT-H&N An lysis Set  
 EQ-5D Analysis Set.   
The FACT-H&N Analysis Set will include all subjects in the Full Analysis Set who 
complete the FACT-H&N assessment at Cycle 1 Day 1, at least partially in a manner that 
permits imputation of missing responses, according to the approach described in Section 
5.6.2.   
The EQ-5D Analysis Set will include all subjects in the Full Analysis Set who complete 
the EQ-5D assessment at Cycle 1 Day 1, at least partially in a manner that permits 
imputation of missing responses, according to the approach described in Section 5.6.2. 
6.2. 
Protocol Deviations 
A list of protocol deviations for the study report will be presented in a data listing. 
6.3. 
Treatment Misallocations 
The following rules of reporting efficacy and safety results (eg, under which treatment 
group) for subjects with errors in treatment allocation will be applied. 
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If subjects are: 
 Randomized but not treated, then they will be reported under their randomized 
treatment group for efficacy analysis.  However, they are by definition 
excluded from the safety analysis as actual treatment is missing. 
 Treated but not randomized, then by definition they will be excluded from the 
efficacy analyses since randomized treatment is missing, but they will be 
reported under the treatment they actually received for all safety analyses. 
 Randomized but took incorrect treatment, then they will be reported under 
their randomized treatment group for all efficacy analyses, but will be 
reported under the treatment they actually received for all safety analyses. 
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7. 
GENERAL STATISTICAL CONSIDERATIONS 
This is a multicenter randomized Phase 2 study designed to evaluate the safety and 
efficacy of patritumab in combination with cetuximab and platinum-based therapy in 
recurrent/metastatic first-line SCCHN. The primary analyses for this study will occur 
when at least 53 PFS events have been observed in the HRG high stratum. 
At the point of primary analysis for PFS, the treatment assignment for all randomized 
subjects will be unblinded to designated study personnel for the analysis after data are 
reconciled and cleaned and a snapshot of the clean database is created. To minimize 
potential bias, subjects and Investigators will not be informed about individual treatment 
assignment until study closure. 
Final analyses will occur after study closure with mature OS data (i.e., when all subjects 
have died or a minimum of 13 months after the last subject is randomized whichever 
comes first). At the time of study closure, subjects who are demonstrating clinical benefit 
(SD or better) from study treatment may be offered an opportunity to continue study 
treatment on the extension phase. 
Assessments of change from baseline to post b seline or the ratio of post baseline to 
baseline will include only those subjects with both baseline and post baseline 
measurements. The last nonmissing value of a variable taken before the first dose of 
study drug will be used as the baseline value, unless otherwise specified. In general, 
missing or dropout data will not be imput d for the purpose of data analysis. Descriptive 
summary statistics (n, mean, median, standard deviation, and range) will be calculated for 
continuous variables, and for categorical variables, the number and percentage in each 
category will be displayed by treatment group. 
Study Day is calculated as <date - 1st study treatment date + 1>. The date of the first 
study treatment is Day 1  
7.1. 
Adjustment for Covariates 
No other covariate adjustments will be applied for primary and secondary efficacy 
analyses, except for the stratification variables if applicable. The PRO analyses will use 
baseline values of the dependent variable as a covariate in a mixed model. 
7.2. 
Handling of Dropouts or Missing Data 
For a description of the handling of censored data for efficacy endpoints such as OS, PFS 
and TTP, see Section 5.1 above. Imputation of partial or missing AE onset date and 
concomitant medication date, incomplete tumor assessment dates, and incomplete dates 
for last contact or death are specified in Section 11.1. The missing data handling for the 
analyses on patient reported outcomes is described in 5.6.2.1. 
7.3. 
Interim Analyses and Data Monitoring 
An independent Data Monitoring Committee (DMC) will be established for this study 
and will review the ongoing safety of the study participants and monitor the overall 
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conduct of the clinical trial. The DMC will review accumulating safety data at periodical 
basis. Based on its ongoing review of the unblinded safety data, the DMC will outline 
any serious safety concerns and make recommendations to continue, modify, suspend, or 
terminate the study. 
Details on the membership, responsibilities and working procedures of the Independent 
DMC will be described in the DMC Charter, provided as a separate document in the 
study file. The same independent Data Analysis Group statistician responsible for 
providing the safety data will also provide efficacy data (for proper assessment of the 
risk/benefits of continuing treatment and study) to the DMC for review. 
7.4. 
Multicenter Studies 
There will be approximately 35 sites in Europe. Site as a factor will not be formally 
examined in this study. 
7.5. 
Multiple Comparisons/Multiplicity 
This study has only one primary efficacy variable PFS. The testing hypotheses to 
compare PFS the patritumab arm versus the control arm will be performed in two 
sequential steps in pre-defined populations (Freidlin 2012 et al). The primary analysis is 
PFS comparison between the patritumab arm and the control arm in HRG-high stratum of 
the FAS (Step 1). If the testing in Step 1 is significant, then no further testing will be 
performed in Step 2 and the 80% confid n e intervals of the hazard ratio in HRG low 
stratum will be estimated. If the testing in Step 1 is not significant, then the testing in 
FAS (HRG high + low) will be performed in Step 2 (See Section 8.2.1). The results from 
both steps will be used to guide the decision on future Phase 3 designs. Since this is a 
proof of concept study, no adjustment for multiplicity will be performed. 
7.6. 
Examination of Subgroups 
As exploratory analyses, subgroup analysis (e.g. age, sex, HRG, HPV, primary tumor 
site, etc) for selective efficacy endpoints will be conducted (Section 8.2.4). 
 
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8. 
STATISTICAL ANALYSIS 
8.1. 
Study Population Data 
8.1.1. 
Subject Disposition 
Subject disposition will be summarized by randomized treatment group and overall for 
All Screened Subjects. The number and percentage of subjects in the Full Analysis Set, 
the Per Protocol Analysis Set, the Safety Analysis Set, the Pharmacokinetics Analysis 
Set, and the PRO Analysis Sets will be presented. Subject status (ongoing, if any, and 
discontinued from study treatment) and the reasons for discontinuation (as reported on 
CRF EOT page) will be summarized in this table. All percentages, except those for All 
Screened Subjects, will be based on the Full Analysis Set. A listing will present data 
relevant to subject disposition. 
8.1.2. 
Protocol Deviations 
Protocol deviations collected by clinical team, as well as those identified in the CRF data 
will be provided in a listing. 
Protocol deviations will be finalized prior to database lock. 
8.1.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group and 
overall for the FAS as well as the HRG-high stratum of the FAS, Per-Protocol analysis 
set (if substantial differences such as >5% as compared to the FAS), and Safety Analysis 
Set. If two sets of subjects are dentical to each other, analysis will only be performed 
once. 
Demographic characteristics consist of age, gender, race, and ethnicity. A subject’s age in 
years is calculated using the informed consent date and the birth date [(consent date-
birthdate)/365.25]. Age will additionally be categorized as (≤ 65, > 65) for reporting 
purposes. 
Baseline characteristics consist of height, weight, tumor stage at study entry, tumor grade, 
prior systemic cancer therapy (Yes or No), prior radiation therapy (Yes or No), time from 
diagnosis of SCCHN to study treatment, histology subtype, HRG value, HPV Status, 
tobacco history (cigarettes and cigars), ECOG performance status, and ECG findings at 
baseline.  
Individual subject listings of all demographic, baseline characteristics, SCCHN cancer 
history, medical and surgical history including prior cancer history and prior cancer 
surgery, and prior cancer therapy will be provided. 
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8.2. 
Efficacy Analyses 
Efficacy analyses will be performed on the FAS and per-protocol analysis set as well as 
HRG strata. Subjects will be analyzed according to the treatment assigned at 
randomization. 
8.2.1. 
Analysis of Primary Efficacy Variables 
The primary efficacy endpoint is PFS as defined in Section 5.1.1 of this SAP. Progression 
will be determined based on the investigators’ assessment. 
The primary efficacy analysis will be the comparison of PFS between the patritumab arm 
and the control arm in HRG-high stratum of the FAS using the stratified log-rank test. 
For a description of the handling of censored data for efficacy endpoint PFS, see Section 
5.1 above.  
The testing hypotheses to compare PFS for the patritumab arm versus the control arm 
will be performed in two sequential steps (Freidlin 2012 et al). In step 1, the null 
hypothesis that PFS is the same for both arms in the HRG high stratum of FAS is tested 
at the one-sided 0.10 significance level. If this test in step 1 does not reject the null 
hypothesis, then in step 2A, the null hypothesis that PFS is the same for both arms in the 
FAS (HRG high stratum + low stratum) will be t s ed at the one-sided 0.05 significance 
level. If the test in step 1 is rejected, then in st p 2B, the two-sided 80% confidence 
interval (CI) for hazard ratio (HR) of PFS in the HRG low stratum of the FAS will be 
estimated. 
The comparison of PFS between the patritumab arm and the control arm will be 
performed using a log-rank test stratified by the stratification factors.  
Hypothesis testing for superioritywith regard to PFS will be performed with a 1-sided 
hypotheses setting.   
Suppose that SA(t) and SP(t) are the cumulative survival functions for PFS in patritumab 
and control treatment groups, respectively.  The null hypothesis H0 with PFS: 
H0:   
SA(t) = SP(t) for all t ≥ 0  (identical survival functions for both groups) 
will be tested against the 1-sided alternative hypothesis HA: 
HA:  
SA(t) ≥ SP(t) for all t ≥ 0 and SA(t) > SP(t) for at least some t > 0 
(improvement in PFS in the patritumab group over the control group) 
The stratified log-rank test will be conducted using SAS PROC LIFETEST where the 
STRATA statement will include the treatment group and the stratification factors [HPV 
(positive vs other) and HRG (high vs. low, only for the FAS) at randomization]. The 1-
sided p-value will therefore be obtained and H0 will be rejected if p-value ≤ the pre-
specified 1-sided alpha.  
The Kaplan-Meier product-limit method will be used to estimate the distribution of PFS 
for the patritumab arm versus the control arm. The median PFS for each treatment group 
will be based on the Kaplan-Meier estimate and the 95% confidence intervals for each 
treatment group will be calculated using the method of Brookmeyer and Crowley. The 
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median and confidence interval will be reported in months, and days will be converted to 
months by dividing by 30.4. The corresponding Kaplan-Meier curves will also be 
presented.  
Estimates of HR between 2 arms along with their two-sided 80% and 95% CIs will be 
calculated using stratified Cox proportional hazards regression model. SAS PROC 
PHREG with the treatment group as the model covariate and stratification factors [HPV 
(positive vs other) and HRG (high vs. low) at randomization] as the STRATA variables 
will be used for this model. The Efron’s method will be used to handle ties.   
The above analysis for PFS will be repeated for the per-protocol analysis set. A separate 
analysis which includes clinical progression as a PFS event will be done as a sensitivity 
analysis. 
8.2.2. 
Analysis of Secondary Efficacy Variables 
8.2.2.1. 
Overall Survival 
OS will be analyzed in the same manner as for PFS. Estimates of HR between the 
patritumab arm and the control arm along with their two-sided 80% and 95% CIs will be 
calculated using stratified Cox proportional hazards regression model. SAS PROC 
PHREG with the treatment group as the model covariate and stratification factors at 
randomization as the STRATA variables will be used for this model. The Efron’s method 
will be used to handle ties. The corresponding Kaplan-Meier curves will also be 
presented. 
8.2.2.2. 
Objective Response Rate 
The number and the percentage of the subjects with the best overall tumor responses of 
either CR or PR (the objective response) will be tabulated by treatment group. 
Percentages will be calculated based on the number of subjects in the respective 
treatment group. The differences in the ORR between the control arm and patritumab arm 
will be presented along with two-sided 80% and 95% CIs based on the Wilson’s score 
method with continuity correction. 
In addition, the percent change from baseline will be calculated for the sum of longest 
diameters (LD) for all target lesions at each post-treatment evaluation for each subject, if 
applicable. The percent change in the sum of longest diameters from baseline in target 
lesions will be summarized by treatment group and assessment time with descriptive 
statistics; the largest decrease from baseline will also be summarized and displayed in the 
waterfall plots.  
Best overall response and tumor assessments (target lesions, non-target lesions and 
overall) will be listed for all subjects in the Full Analysis Set. Percent change from the 
nadir (i.e., minimum sum of LD, including baseline, if that is the minimum value, up to 
the preceding tumor assessment) will be presented in the listing for target lesions. 
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8.2.2.3. 
Cutoff for HRG Expression 
HRG expression value will be summarized by treatment group for overall, HRG-high, 
and HRG-low group with summary statistics. The distribution of HRG values will be 
plotted with histogram and normal curves.  
HRG expression values will be dichotomized at alternative cutoffs to form new HRG-
high and HRG-low groups. Analysis of PFS and OS specified in Section 8.2.1 and 
Section 8.2.2.1 will be performed for newly classified HRG high and low groups at 
alternative cutoffs. The results will be used to select optimum HRG cutoff. 
8.2.3. 
Analysis of Exploratory Efficacy Variables 
Exploratory efficacy endpoints include duration of response, time to response, time to 
disease progression, and duration of SD. 
8.2.3.1. 
Duration of Response 
The distribution of duration of response as defined in Section 5.1.4.1 of this SAP will be 
presented as Kaplan Meier plot, together with response duration quartiles for responding 
subjects (PR or CR). Median time to response will be stimated along with two-sided 
80% and 95% CIs using Kaplan-Meier methods   
8.2.3.2. 
Time to Response 
The distribution of time to response as defined in Section 5.1.4.2 of this SAP will be 
presented as Kaplan Meier plot, together with response duration quartiles for responding 
subjects (PR or CR). Median time to response will be estimated along with two-sided 
80% and 95% CIs using Kaplan Meier methods. 
8.2.3.3. 
Time to Disease Progression 
Median time to disease progres ion will be estimated along with two-sided 80% and 95% 
CIs using Kaplan-Meier methods by treatment. In addition, summary statistics for 25% 
and 75% percentiles will be estimated using Kaplan-Meier methods. 
8.2.3.4. 
Duration of Stable Disease 
The distribution of duration of stable disease as defined in Section 5.1.4.4 of the SAP will 
be presented as Kaplan Meier plot, together with response duration quartiles for 
responding subjects with the best response of stable disease. In addition, median duration 
of stable disease will be estimated along with two-sided 80% and 95% CIs using Kaplan-
Meier methods. 
8.2.4. 
Sensitivity and Subgroup Analysis 
8.2.4.1. 
Sensitivity Analysis 
Sensitivity analysis for PFS will be performed by including both RECIST progression 
disease and clinical progression as PFS events. If HRG cutoff is changed during subject 
enrollment and stratification, the subject HRG status (High versus Low) will be redefined 
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using the changed HRG cutoff into new HRG high and low cohorts. Statistical analysis 
for PFS and key secondary endpoints will be conducted for the new HRG cohorts as a 
sensitivity analysis.  
8.2.4.2. 
Subgroup Analysis 
The subgroup analyses for PFS and OS specified in Section Error! Reference source 
not found. and Section Error! Reference source not found. will be performed for the 
subgroups below if data warrants: 
 Age (≤65, > 65 yrs) 
 Sex (Female, Male) 
 Race (White, Non-white) 
 HPV status (Postive, Negative) 
 HRG subgroups (alternative cutoffs) 
 Primary tumor site (oral cavity, oropharynx, hypopharynx, and larynx) 
 ECOG performance status (0, 1) 
 Platinum-based therapy (cisplatin  carboplatin; n.b., subjects treated with both 
will be excluded) 
 Tumor grade (well- or mod rately differentiated, poorly differentiated) 
 Previous treatment (neoadjuvant chemotherapy, radiochemotherapy) 
 Baseline FACT-H&N total score (≤ median, > median) 
A Cox proportional hazards regression with treatment as the only covariate will be 
applied. Forest plots will be presented for both PFS and OS. 
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8.3. 
Safety Analyses 
All analyses involving safety data (extent of exposure, TEAEs, clinical laboratory results, 
vital signs, ECG, echocardiograms/MUGAs, physical exam, HAHA, and ECOG 
performance status) will be performed on the Safety Analysis Set. No inferential 
statistical analysis is planned for safety data.  Descriptive statistics will be calculated for 
quantitative safety data and frequency counts and percentages will be compiled for 
classification of qualitative safety data. All percentages will be calculated based on the 
number of subjects in the Safety Analysis Set. If the number of subjects with available 
data does not allow for the reliable estimation of variability at a scheduled time point, no 
summary statistics will be presented for that time point.  Unless otherwise noted, baseline 
values will be the last non-missing assessment collected prior to first dose of study drug. 
8.3.1. 
Adverse Events 
A treatment-emergent AE (TEAE) is defined as an adverse event that has an onset date 
on or after the first dose of patritumab/Placebo, or worsens in severity after the first dose 
of patritumab/Placebo relative to the pre-treatment state. An adverse event that occurs 
more than 30 days after the last dose of study medication will not be included as a TEAE, 
unless it is considered drug related.   
Adverse events will be coded using the Medic l Dictionary for Regulatory Activities 
(MedDRA) and summarized for the number and percentage of subjects reporting 
treatment emergent AEs. AEs/toxicities and laboratory test results (hematology and blood 
chemistry) will be graded according to the NCI CTCAE, Version 4.03. The number and 
percentage of subjects reporting TEAEs will be tabulated by the worst CTCAE grade, 
system organ class, and preferred term  with a breakdown by treatment group. Similarly, 
the number and percentage of subjects reporting treatment emergent serious adverse 
events (SAEs) will be tabulated, as well as TEAEs and treatment emergent SAEs 
considered related to patritum b, cetuximab, and cisplatin/carboplatin. 
At each level of subject summarization, a subject will be counted once if he/she reports 
one or more occurrences of the same system organ class/preferred term/grade. For 
treatment-emergent (serious) adverse event toxicity tables tabulated on subject level, a 
subject with two or more treatment-emergent adverse events with the same preferred term 
will be counted only once for that term using the most severe toxicity. For a given 
subject, if the toxicity grade is missing for all treatment-emergent adverse events with the 
same preferred term, the treatment-emergent  adverse events will be counted only once 
for that term under the “Missing” CTCAE toxicity category. In the presence of a subject 
who has both missing and non-missing CTCAE toxicity grades for adverse events with 
the same preferred term, the missing CTCAE toxicity of the adverse event will be treated 
as the lowest toxicity grade. In addition, a subject who reported two or more treatment-
emergent adverse events with the same system organ class will be counted only once in 
the system organ class total, and subjects with two or more treatment-emergent adverse 
events in different system organ classes will be counted only once in the overall total. 
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A by-subject AE (including treatment emergent) data listing including, but not limited to, 
verbatim term, preferred term, system organ class, CTCAE grade, and relationship to 
study drug will be provided. 
SAEs reported from tumor biopsies collected during Screening will be recorded, but not 
included in the primary analysis. 
Deaths, other SAEs, and other significant AEs, including those leading to permanent 
discontinuation of subjects from patritumab, cetuximab, and cisplatin/carboplatin will be 
listed. 
8.3.2. 
Clinical Laboratory Evaluations 
For continuous laboratory parameters, values and their changes from baseline at each 
visit will be summarized, as well as the maximum and minimum post-treatment values, 
and values for the last observation on treatment. Last observation on treatment is defined 
as the last non-missing value on or prior to end of treatment duration plus 7 days. 
Repeated or unscheduled tests will not be summarized fo  each scheduled visit, but will 
be included for summaries of maximum and minimum post-treatment values.  
Clinical laboratory test results (hematology and blood chemistry) will be graded 
according to the NCI CTCAE, Version 4.03. Test results will also be flagged as low or 
high relative to the normal reference ranges. For each test, subjects will be characterized 
based on their worst severity grade observed during post-baseline period, based on 
CTCAE criteria and/or normal reference ranges. For parameters where CTCAE criteria 
are applicable, a shift table presenting the 2-way frequency tabulation of baseline and the 
worst post-baseline CTCAE grades will be provided. If absolute neutrophil or 
lymphocyte counts are not reported in the lab data, but percent differentials and total 
WBC are available, the absolut  counts will be derived by the formula: differential count 
= 100*differential(%)/WBC  and will be reported with the same units as WBC. Derived 
differentials will be used for NCI-CTCAE toxicity grading, and will not be reported with 
a normal range. Derived values that do not meet the NCI-CTCAE criteria for grade 2 or 
higher toxicity will be reported as grade <1 and as being within normal range. If the 
result of a liver function test is below a certain threshold (e.g., AST reported as <10), then 
it will be reported as grade <1 and as being within normal range. 
Abnormal clinical laboratory test results deemed of clinical significance or of CTCAE 
Grade 3 or 4 will be listed. 
8.3.3. 
Liver Function Parameters 
Subjects with elevated post-baseline ALT, AST or Total Bilirubin that fall into the 
following categories will be identified. Number and percentage of these subjects will be 
tabulated for each cohort and in total. 
 AST >= 3 × Upper Limit of Normal range (ULN) 
 ALT >= 3 × ULN 
 AST >= 3 × ULN or ALT >= 3 × ULN 
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 AST >= 5 × ULN 
 ALT >= 5 × ULN 
 AST >= 5 × ULN or ALT >= 5 × ULN 
 Total Bilirubin  >= 2×ULN 
 AST >= 3 × ULN  and Total Bilirubin  >= 2×ULNa 
 ALT >= 3 × ULN  and Total Bilirubin  >= 2×ULN 
 (AST >= 3 × ULN  or ALT >= 3 × ULN)   and Total Bilirubin  >= 2×ULN 
Total Bilirubin  >= 2×ULN is defined as at least one case of post-dose ≥ 2 x ULN 
occurred between the first incidence date and 30 days after the last incidence date of 
ALT ≥ 3 x ULN post treatment. Same rule applies to the last 2 categories. 
8.3.4. 
Vital Signs 
Values and change from baseline for vital signs, incl ding systolic blood pressure, 
diastolic blood pressure, pulse, body temperature, and weight will be summarized by 
treatment group and scheduled time of evaluation (including end-of-treatment visit), as 
well as for the maximum and minimum post-treatment values, the values at the end-of-
treatment visit, and values for the last observation on treatment for the Safety Analysis 
Set. Last observation on treatment is defined as the last non-missing value on or prior to 
end of treatment duration plus 7 days. 
Repeated or unscheduled tests will not be summarized for each scheduled visit, but will 
be included for summaries of maximum and minimum post-treatment values. A 
comprehensive listing of vital signs will be provided. 
8.3.5. 
ECG 
Values and change from baseline for ECG parameters, including heart rate, PR interval, 
RR interval, QRS duration, QT interval, QTcB (QT / RR**1/2), and QTcF (QT / 
RR**1/3), will be summarized for each treatment group and in total at scheduled time of 
evaluation (including end-of-treatment visit). 
In addition, the following notable ECG interval values for each parameter will be 
evaluated: 
QTcB and QTcF:  
 New >450 msec  
 New >480 msec  
 New >500 msec  
 Increase from baseline >30 msec  
 Increase from baseline >60 msec  
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Note that “New” implies a newly occurring ECG abnormality. It is defined as an 
abnormal ECG finding at post-baseline that is not present at baseline, e.g., QTc New > 
480 msec implies QTc > 480 msec pose-baseline and QTc ≤  480 msec at baseline.  
A subject with multiple occurrences of a newly occurring abnormality is counted only 
once per abnormality. 
The percentage of subjects with newly occurring qualitative ECG abnormalities is based 
on the total number of subjects who are at risk of developing this abnormality in the 
category. For each individual abnormal finding, this is defined as the number of subjects 
with both baseline and post baseline evaluations and a normal value at baseline.  
If a QTc record is missing but the records of QT interval and RR are available then QTc 
should be derived using the formula above. If RR is missing but heart rate (HR) is 
available, QTc should be derived using the following formulae:  
 QTcF = QT x (HR/60)1/3 
 QTcB = QTx (HR/60)1/2 
Data from ECGs will also be presented in the data listings using the Safety Analysis Set. 
8.3.6. 
Dosing and Extent of Exposure 
The number of IV received will be summarized for patritumab, cetuximab, and 
cisplatin/carboplatin, respectively, for subj cts in Safety Analysis Set.  
Treatment duration in weeks for patritumab and cisplatin/carboplatin is calculated as 
(date of the last dose – date of the first dose + 21)/7.  
Cycle duration in days is calculated as (date of Day 1 of next cycle – date of Day 1 of 
present cycle). Cycle duration is not calculated for the last cycle. Average cycle duration 
will be calculated for each subject. 
Treatment duration for cetuximab is calculated as Duration (weeks): (date of the last dose 
– date of the first dose + 7)/7 
For all study treatment expect carboplatin: 
 Total cumulative dose (mg/kg) is defined as the sum of all doses (mg/kg) taken by 
a subject. 
 Total cumulative dose (mg) is calculated as total cumulative dose (mg/kg) x 
weight (kg).  
 Dose intensity (mg/kg/cycle/dose) is calculated as 3*(total cumulative 
dose(mg/kg)/(Duration(weeks)*(number of planned doses/cycle)) 
 Relative dose intensity (%) is calculated as 100*(dose intensity/(planned protocol 
dose) 
For carboplatin: 
 Total cumulative dose (mg) is defined the sum of all doses (mg) taken by a 
subject. 
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 Dose intensity is calculated as 3*(total cumulative dose(mg)/Duration(weeks) 
 Relative dose intensity (%) is calculated as 100*(dose intensity)(planned protocol 
dose (mg)) where the planned protocol dose is 5x(creatinine clearance + 25) (i.e., 
target of 5 AUC), and the creatinine clearance is calculated using the modified 
Cockcroft-Gault equation (Protocol Appendix 17.1). 
For the purpose of counting cycle, a subject is considered to be treated in a cycle if they 
receive the Day 1 dose. Treatment duration (in weeks and cycles), total cumulative dose, 
dose intensity, relative dose intensity, doses not completed, dose reductions, and number 
of IV received will be summarized using descriptive statistics, and listed for each subject 
in the Safety Analysis Set. Average cycle duration and number of cycles delayed, defined 
as time from last cycle > 21 days,) will be reported for patritumab. Subjects’ dose 
modification will also be listed for patritumab, cetuximab, and cisplatin/carboplatin. 
8.3.7. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using he World Health Organization 
(WHO) drug dictionary. Prior and concomitant medications will be summarized by 
treatment group, ATC2 class, and preferred term. A subject who takes one or more 
medications under any given ATC2 class and preferred term will be counted once for the 
ATC2 class and preferred term. 
For the summary, medications taken prior to the first dose of study medication will be 
classified as prior medications, while medications taken on or after the first dosing will 
be classified as concomitant medications. Medications taken prior to the first dosing but 
with a missing stop date or with a stop date either on or after the first dosing or marked as 
“continuing” will also be conside ed c ncomitant medications for the summary. A listing 
of prior and concomitant medications by subject will be provided for the Safety Analysis 
Set. 
8.3.8. 
Physical Examinations 
A listing of physical examination data by subject for the Safety Analysis Set will be 
provided. 
8.3.9. 
Analysis of Other Safety Variables 
HAHA results (positive as determined by titer values, if positive on screening, and 
detection of neutralizing antibody, if needed) will be listed to identify subjects with 
positive HAHA.  
ECOG performance status at baseline and scheduled time of evaluation (including end of 
Treatment visit) will be summarized by treatment group and in total for Safety Analysis 
Set. A two-way frequency tabulation for baseline and each study visit will be provided 
for ECOG performance status.  
Left ventricular ejection fraction (LVEF) will be summarized using descriptive statistics 
for actual values and for changes from baseline by cohort by scheduled time of evaluation 
including the end of treatment visit as well as for the minimum and maximum post-
baseline values and for the last observation on treatment. The last observation on 
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treatment value is defined as the last non-missing value on or prior to end of treatment 
duration plus 7 days. Repeated or unscheduled tests will not be summarized for each 
scheduled visit, but will be included for summaries of maximum and minimum post-
baseline values and the last observation on treatment. 
A listing of ECOG performance status will be presented. 
A listing of echocardiogram by subject for the Safety Analysis Set will be provided. 
8.4. 
Pharmacokinetic Analyses 
8.4.1. 
Concentration Data 
 Concentrations below the lower limit of quantitation (BLQ) will be set to zero for the 
calculation of descriptive statistics.  If any of the concentrations at a time point is BLQ, 
the geometric mean of the concentrations at this partic lar time point will not be 
calculated and will be presented as “NC” in the summary t bles. PK data will be listed 
for the pharmacokinetic analysis sets. 
8.4.1.1. 
Sparse Patritumab PK 
Serum concentrations for patritumab at Cycles 1-3 and at End of Study Treatment will be 
listed and summarized with descriptive statistics using the PK Analysis set. Mean plasma 
concentration of patritumab versus time will be plotted on both linear scale and semi-
logarithm scale. 
8.4.1.2. 
Intensive PK 
Intensive PK refers to samples taken during Cycle 1 (Day 1 to Day 21 for patritumab, 
Day 1 to Day 8 for cetuximab  Day 1 to Day 3 for cisplatin or carboplatin). Individual 
concentration profiles versus tim  by treatment group for each study drug will be plotted 
on linear and logarithmic scal s  Concentrations will be summarized by treatment and 
nominal timepoint. Individual PK parameters will be listed and summarized by treatment.  
The PK parameters, area under curve at last time point (AUClast) and Cmax will be 
summarized and listed by treatment groupfor each drug using the PK Analysis set. Box 
plots of AUClast and Cmax versus treatment will be presented. 
8.4.2. 
Analysis of Pharmacokinetic (PK) Parameters  
The intensive PK parameters, area under curve at last time point (AUClast) and Cmax will 
be summarized and compared for cetuximab and platinum concentration by treatment 
arms for the PK Analysis set. The possible drug-drug interactions between patritumab 
plus cetuximab or cisplatin/carboplatin, the PK of serum cetuximab and platinum 
concentrations will be compared with and without patritumab using an ANOVA model 
with treatment as factor. AUClast and Cmax will be log-transformed prior to analysis. The 
geometric mean ratios and their two-sided 90% CIs for AUClast and Cmax between the 
patritumab arm and the placebo arm will be calculated using the exponentiation of the 
differences and their CIs between treatments least square mean from the ANOVA. The 
ratios and their two-sided 90% CIs will be expressed relative to the placebo arm.  
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8.4.3. 
Population Pharmacokinetic (PK) and Exposure Response 
For all subjects, sparse samples for serum patritumab concentrations will be assessed 
using population PK methods. The relationship between exposure and response will be 
explored using population PK modeling. These analyses are outside the scope of this SAP 
and details of those analyses will be included in a separate document for population PK 
and exposure response analyses. 
8.5. 
Pharmacodynamic (PD) Parameters 
Not Applicable. 
8.6. 
Biomarkers Analyses 
The study has baseline HRG biomarker and HPV status assessments to determine the 
stratification factors of HRG and HPV. Baseline HRG cutoff will be used for all specified 
efficacy analyses. As exploratory analyses, the HRG cutoff will be refined using graphic 
technique, data distribution, maximum likelihood methods, and clinical benefit of HRG 
high group. Selected efficacy analyses for the HRG high stratum will be performed using 
the refined HRG cutoff as additional exploratory analyses. Further biomarker evaluations 
will be summarized descriptively. 
Baseline HRG values will be summarized and listed. 
8.7. 
Other Variables Analyses 
8.7.1. 
Patient Reported Outcomes 
The FACT-H&N total score (FACT-G +disease specific subscale score), the FACT-H&N 
individual subscale scores (Physical Well Being (PWB), Social Well Being (SWB), 
Emotional Well Being (EWB), Functional Well Being (FWB)), FACT-G total score, and 
the FACT-H&N FHNSI sco  and change from baseline will be summarized by visit and 
treatment group using the FACT-H&N Analysis Set.  
For each post-baseline assessment: 
- 
Observed range; Mean (SD) by treatment group (overall, HPV+ and HPB-) will 
be reported for each of the scores listed above. 
- 
The entire Cumulative Distribution Function (CDF) of change from baseline on 
FACT-G, FACT-H&N FHNSI and FACT-H&N total score will be presented as a 
continuous plot of the change from baseline on the X-axis and the cumulative 
percent of subjects experiencing that change on the Y-axis for each treatment 
group.  
Change from baseline in the FACT-H&N total score (FACT-G +disease specific subscale 
score), the FACT-H&N individual subscale scores, FACT-G total score, and the FACT-
H&N FHNSI score, will also be evaluated using mixed longitudinal modeling for the 
FACT-H&N Analysis Set. The model will include treatment, time, treatment-by-time 
interaction, and baseline as fixed effects. The unstructured option for the REPEATED 
statement in PROC MIXED will be used to model the within subject covariance 
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structure. LS means along with 95% CIs by timepoint and LS mean differences between 
the control arm and patritumab arm along with two-sided 95% CIs for each timepoint will 
be derived.  
For these analyses, PRO values obtained at the end of treatment visit or at any scheduled 
timepoint with fewer than 5 subjects in the placebo arm or patritumab arm will not be 
included.   
Descriptive statistics for the actual value and change from baseline will be computed for 
the EQ-5D-5L health profile utilities and EQ-5D VAS by scheduled time of evaluation 
(including end of treatment visit) for all subjects and by treatment group using the EQ-5D 
Analysis Set.  Results of the EQ VAS will be presented as a measure of overall self-rated 
health status.   
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9. 
CHANGES FROM THE PROTCOL SPECIFIED 
STATISTICAL ANALYSES 
No changes have been issued. 
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10. 
REFERENCES 
1. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am 
J Clin Oncol. 1982;5:649 55. 
2. Cella DF. Manual: Functional Assessment of Cancer Therapy (FACT) Scales and 
Functional Assessment of HIV Infection (FAHI) Scale. Chicago: Rush-
Presbyterian-St. Luke's Medical Center (1994). 
3. D'Antonio LL, Zimmerman GJ, Cella DF, & Long, S.A. Quality of life and 
functional status measures in patients with head and neck cancer. Arch 
Otolaryngol Head Neck Surg. 1996; 122, 482-487. 
4. Yount S, List M, Du H, et al. A randomized validation study comparing 
embedded versus extracted FACT head and neck symptom index scores. Qual 
Life Res. 2007;16:1615-26. 
5. The EuroQol Group (1990). EuroQoL-a new facility for the measurement of 
health-related quality of life. Health Policy. 1990;16(3):199-208. 
6. Brooks R. EuroQoL: the current state of play. Health Policy. 1996; 37(1):53-72. 
7. Freidlin B, McShane LM, Polley M-Y C, et al. Randomized phase II trial designs 
with biomarkers. J Clin Oncol  2012;30:3304-3309. 
8. Kaplan, E. L.; Meier, P. (1958). "Nonparametric estimation from incomplete 
observations". J. Amer. Statist. Assn. 53 (282): 457–481. 
9. Brookmeyer, R. and Crowley, J. (1982), “A Confidence Interval for the Median 
Survival Time,” Biometrics, 38, 29–41. 
10. Newcombe, R. (1998). Two-Sided confidence intervals for the single proportion: 
comparison of seven methods. Statistics in Medicine,17, 857-872. 
11. Newcombe, R. (1998). Interval estimation for the difference between independent 
proportions: comparison of eleven methods. Statistics in Medicine,17, 873-890 
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 If the year is present and the month and day are missing or the year and day 
are present and the month is missing, set month and day to January 1. 
 If the year and month are present and the day is missing, set day to 1st day of 
month. 
 If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
If the end date of medication is completely missing which the day, month, and year are 
all unknown or only the day is known, then the end date will not be imputed. 
For the partial end date of medication, 
 If the year is present and the month and day are missing or the year and day 
are present and the month is missing, set month and day to December 31. 
 If the year and month are present and the day is missing, set day to last day of 
the month. 
 
Incomplete Tumor Assessment Dates 
All dates for tumor assessment must be completed with day, month and year. 
 If one or more measurement dates (e.g. X-ray, CT-scan for target and non-
target tumor lesions) are incomplete but other measurement dates are 
available, this/these incomplete date(s) are not considered for calculation of 
the assessment date. 
 If all measurement dates have no day recorded, the 1st of the month is used. 
 If the month is not completed, for any of the assessments, the respective 
assessment will be onsidered to be at the midpoint of previous and following 
assessment dates.  
 
Incomplete Dates for Last Contact or Death 
All dates are expected to be completed with day, month, and year.  
If the day/month is missing, the 1st of the month/year will be used for incomplete death 
dates or dates of last contact. 
 
 
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11.2. 
Interim Analysis Statistical Analysis Plan 
Safety data and efficacy data will be prepared for the purpose of DMC reviews, and the 
frequency and extent of such data reviews will follow the DMC charter for Study 
U31287-A-U203. In general, the statistical methodology and TLF shells in the SAP will 
be a framework to generate outputs for DMC reviews. The independent Data Analysis 
Group (DAG) will perform the analysis. Operating details of the DAG are included in the 
DMC charter. 
 
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11.3. 
Formula for Wilson Method  
Wilson Method 
Use the following formula to compute a (1-% confidence interval for a single 
proportion using the Wilson method with continuity correction: 
  
 ̂    
     
     √ ̂ [  (   ̂ )   ]
   
         
⁄
   
 
    
  
 
  
 ̂    
     
     √ ̂ [  (   ̂ )   ]
   
         
⁄
   
 
    
  
 
where  denotes the sample proportion for group i and the group sample size.  All 
statistical constants will be computed using appropriate SAS functions. Note: if =0, L 
must be taken as 0; if =1, U is then 1. In case L is calculated to be less than 0, set L to 0; 
and similarly set U to 1 if U is calculated to be larger than 1. 
Confidence limits for the difference in ORR between each of the U3-1287 (AMG888) 
groups and placebo based on Wilson (Newcombe) score will use the method below. 
Denote the lower and upper Wilson score (with continuity correction) confidence limits 
for p1 as L1 and U1 and the lower and upper confidence limits for p2 as L2 and U2 (where 
L and U are defined above). The Wilson score (with continuity correction) confidence 
limits for the proportion diff ence (d=p1-p2) are computed as 
 
 
 
 
 
ipˆ
n
ipˆ
ipˆ
2
2
2
1
1
1
2
1
/)
1(
/)
1(
)
ˆ
ˆ
(
n
U
U
n
L
L
z
p
p
dL






2
2
2
1
1
1
2
1
/)
1(
/)
1(
)
ˆ
ˆ
(
n
L
L
n
U
U
z
p
p
dU






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11.4. 
Mock-up Tables and Listings 
The date on which the first dose of study medication (including placebo) is administered 
is considered as Day 1 of the study. For events occurring on or after the start of treatment, 
study day is calculated as the event date minus the date of first administration of study 
medication plus 1 day.  For events occurring before the start of treatment, study day is 
calculated as the event date minus the date of first administration of study medication. 
Raw measurements will be reported to the number of significant digits as captured 
electronically or on the CRF. The mean and median will be displayed to one decimal 
place beyond the number of decimal places the original parameter is presented, and the 
measure of variability (e.g., standard deviation) will be displayed to two decimal places 
beyond the number of decimal places the original parameter is presented.  Minimums and 
maximums will be reported to the same number of significant digits as the parameter. 
Calculated percentages will be reported with 1 decimal place.  When count data are 
presented as category frequencies and corresponding percentages, the percent will be 
suppressed when the count is zero. Show a ‘Missing row’ after the last category if there 
are missing observations for the variable. 
P-values will be reported to 4 decimal places (SAS format pvalue6.4). Values less than 
0.0001 will be displayed as <0.0001. Values greater than 0.9995 will be displayed as 
1.0000. Unless otherwise indicated, 1-sided p-values are presented in the tables.   
All tables will summarize data for the overall study population and by the high and low 
HRG expression strata. For disposition tables and safety tables the order will be overall, 
high, and low. For efficacy tables the order will be high, low, and overall. 
Listings will be presented for each part and sorted by subject ID. When available, listings 
will also be sorted by study day.  
Unless otherwise indicated  continuous variables will be summarized using the following 
descriptive statistics: the number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. The frequency and percentage of observed levels will be 
reported for categorical measures. Percentages will be based on the number of subjects in 
the relevant analysis set.  All statistical analyses will be performed in SAS Version 9.1 or 
higher 
 
 
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Table 15.1.1: Subject Disposition 
All Screened Analysis Set 
HRG High 
Subject Accounting 
Patritumab + cetuximab + 
cisplatin or carboplatin  
(N=xxx) 
Placebo + cetuximab +  
cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
 
 
 
 
 
 
 
Screened 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screened, But Not Randomized 
 
 
 
 
 
xxx [a] 
 
 
 
 
 
 
 
Randomized 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomized but Not Dosed 
 
xxx (xx.x) 
 
xxx ( x.x) 
 
xxx (xx.x) 
 
 
 
 
 
 
 
 
Analysis Set 
 
 
 
 
 
 
          Full Analysis Set (Intent to Treat Set)[b] 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
          Safety Analysis Set 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
          Per-Protocol Analysis Set 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
          PK Analysis Set 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
          FACT-H&N Analysis Set 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
          EQ-5D Analysis Set 
 
xxx (xxx ) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
 
 
 
 
 
 
Treatment Status 
 
 
 
 
 
 
    Ongoing on the Study Treatment 
 
xx  (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
    Discontinued from Study Treatment 
 
xxx 
xx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
    Primary Reason for Discontinuation from         
Study Treatment 
 
 
 
 
 
 
          Adverse Event 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Progressive Disease per RECIST 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Clinical Progression 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Lost to Follow-up 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Death 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Protocol Violation 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Withdrawal by subject 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Study Terminated by Sponsor 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Other 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
Notes: Percentages are based on the number of subjects in the Full Analysis Set. 
           [a] Subjects who had signed ICF and were screened but not randomized are not included in the total number of Full Analysis Set. 
           [b] The full analysis set (FAS) will be based on the intent-to-treat principle and will include all subjects randomized into the study. 
           [c] On-study Death is defined as death occurred on or after first dose date till 21 days after last dose date of any study drug. 
Source Data: adam.adsl; Listing 16.2.1.1    
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Table 15.1.1: Subject Disposition 
All Screened Analysis Set 
 
HRG High 
Subject Accounting 
Patritumab + cetuximab + 
cisplatin or carboplatin  
(N=xxx) 
Placebo + cetuximab +  
cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
 
 
 
 
 
 
 
Extension Treatment Status 
 
 
 
 
 
 
  Ongoing on the Study Treatment 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
  Discontinued from Study Treatment 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
  Primary Reason for Discontinuation from Study   
Treatment 
 
 
 
 
 
 
          Adverse Event 
 
xxx (xxx.x) 
 
xxx (xxx ) 
 
xxx (xxx.x) 
Clinical Progression 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Lost to Follow-up 
 
xxx (xxx.x) 
 
xxx (xxx x) 
 
xxx (xxx.x) 
Death 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Protocol Violation 
 
xxx (xxx.x) 
 
x (xxx.x) 
 
xxx (xxx.x) 
Withdrawal by subject 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Study Terminated by Sponsor 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Progressive Disease per RECIST 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Other 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
 
 
 
 
 
 
On-Study Death [c] 
 
xxx (xxx.x  
 
xxx (xxx.x) 
 
xxx (xxx.x) 
       Primary cause of  On-Study Death 
 
 
 
 
 
 
         Adverse Event 
 
xx (x x x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
         Disease Progression 
 
xx  (xxx x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
         Unknown 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
         Other 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
 
xxx (xxx.x) 
Notes: Percentages are based on the number of subjects in the Full Analysis Set. 
           [a]: Subjects who had signed ICF and were screened but not randomized are not included in the total number of Full Analysis Set. 
           [b] The full analysis set (FAS) will be based on the intent-to-treat principle and will comprise all subjects randomized into the study.  
           [c] On-study Death is defined as death occurred on or after first dose date till 21 days after last dose date of any study drug. 
Source Data: adam.adsl; Listing 16.2.1.1    
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Table 15.1.2.1: Demographic and Baseline Characteristics 
Full Analysis Set 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
Age (yrs)  [a] 
 
 
 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
 
 
 
 
       <=65 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         >65 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Gender 
 
 
 
Male 
    <=65 
    >65 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Female 
    <=65 
    >65 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Race 
 
 
 
White 
xx (xx. %) 
xx (xx.x%) 
xx (xx.x%) 
Black or African American 
 (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Asian 
xx ( x.x%) 
xx (xx.x%) 
xx (xx.x%) 
American Indian or Alaskan Native 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Native Hawaiian/Pacific Islander 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Other/Specify 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Notes: Denominator for percentages is the number of subjects in the Full Analysis Set.   
            The baseline value is defined as the last non-missing value before initial administration of study treatment. 
            [a]  Age in years is calculated using the informed consent date and the birth date. 
Source Data: adam.adsl; Listing 16.2.4.1, 16.2.4.4.1, 16.2.4.4.2, 16.2.4.4.3, 16.2.4.4.4, 16.2.4.6, 16.2.8.3.2, 16.2.8.3.4, 16.2.8.4.2. 
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Table 15.1.2.1: Demographic and Baseline Characteristics 
Full Analysis Set 
 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
Height (cm) 
 
 
 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
 
 
 
 
Weight (kg) 
 
 
 
n 
xx 
xx 
xx 
Mean 
xx.x 
x x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
 
 
 
 
Histology 
 
 
 
Squamous 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Other 
xx (x x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Histologic Grade 
 
 
 
Well Differentiated 
xx ( x.x%) 
xx (xx.x%) 
xx (xx.x%) 
Moderately Differentiated 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Poorly Differentiated 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Undifferentiated 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Not applicable 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Unknown 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Notes: Denominator for percentages is the number of subjects in the Full Analysis Set.   
            The baseline value is defined as the last non-missing value before initial administration of study treatment. 
            [a]  Age in years is calculated using the informed consent date and the birth date. 
Source Data: adam.adsl; Listing 16.2.4.1, 16.2.4.4.1, 16.2.4.4.2, 16.2.4.4.3, 16.2.4.4.4, 16.2.4.6, 16.2.8.3.2, 16.2.8.3.4, 16.2.8.4.2. 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.1.2.1: Demographic and Baseline Characteristics 
Full Analysis Set 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
Tumor Staging at Study Entry 
 
 
 
         0 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         I 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         IIA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         IIB 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         III 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         IVA 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         IVB 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         IVC 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Time from Initial Diagnosis of SCCHN to Study 
Treatment (month)  [b] 
 
 
 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
<6 months 
xx xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
6-12 months 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
>12 months 
xx (xx.x%  
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Cancer Type 
 
 
 
Oral Cavity 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Oropharynx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Hypopharynx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Larynx 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Notes: Denominator for percentages is the number of subjects in the Full Analysis Set.   
            The baseline value is defined as the last non-missing value before initial administration of study treatment. 
            [a]  Age in years is calculated using the informed consent date and the birth date. 
            [b]  For the partial Initial Diagnosis of SCCHN date, if the month and year are present and the day is missing, then set day to the 1st day of month. 
Source Data: adam.adsl; Listing 16.2.4.1, 16.2.4.4.1, 16.2.4.4.2, 16.2.4.4.3, 16.2.4.4.4, 16.2.4.6, 16.2.8.3.2, 16.2.8.3.4, 16.2.8.4.2. 
Programming Note: continue for HRG Low and Overall on the next page    
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 79 of 190 
Table 15.1.2.1: Demographic and Baseline Characteristics 
Full Analysis Set 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
Cigarette Use 
 
 
 
Current 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Former 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Never 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Duration of Cigarette (years) 
 
 
 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
 
 
 
 
Cigar Use 
 
 
 
Current 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Former 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Never 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Duration of Cigar (years) 
 
 
 
n 
x  
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
Notes: Denominator for percentages is the number of subjects in the Full Analysis Set.   
            The baseline value is defined as the last non-missing value before initial administration of study treatment. 
            [a]  Age in years is calculated using the informed consent date and the birth date. 
            [b]  For the partial Initial Diagnosis of SCCHN date, if the month and year are present and the day is missing, then set day to the 1st day of month. 
Source Data: adam.adsl; Listing 16.2.4.1, 16.2.4.4.1, 16.2.4.4.2, 16.2.4.4.3, 16.2.4.4.4, 16.2.4.6, 16.2.8.3.2, 16.2.8.3.4, 16.2.8.4.2. 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 80 of 190 
Table 15.1.2.1: Demographic and Baseline Characteristics 
Full Analysis Set 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
Prior Systemic  Cancer Therapy 
 
 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Best Response to Prior Systemic  Cancer 
Therapy 
 
 
 
CR 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
PR 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
SD 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
PD 
xx (xx.x%) 
xx ( x.x%) 
xx (xx.x%) 
  Not Applicable 
xx (xx.x%) 
xx (xx %) 
xx (xx.x%) 
          Unknown 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
  Prior Radiation Therapy 
 
 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
  Baseline ECOG Performance Status 
 
 
 
         0 - Fully Active 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         1 - Restricted in Physically Strenuous 
Activity 
xx ( x x%) 
xx (xx.x%) 
xx (xx.x%) 
         2 - Ambulatory and Capable of All Self-
Care 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
         3 – Capable of Only Limited Self Care 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
         4 – Completely Disabled 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Denominator for percentages is the number of subjects in the Safety Analysis Set.   
            The baseline value is defined as the last non-missing value before initial administration of study treatment. 
            [a]  Age in years is calculated using the informed consent date and the birth date. 
Source Data: adam.adsl; Listing 16.2.4.1, 16.2.4.4.1, 16.2.4.4.2, 16.2.4.4.3, 16.2.4.4.4, 16.2.4.6, 16.2.8.3.2, 16.2.8.3.4, 16.2.8.4.2. 
Programming Note: continue for HRG Low and Overall on the next page    
 
 
 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 81 of 190 
 
Table 15.1.2.1: Demographic and Baseline Characteristics 
Full Analysis Set 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
Baseline 12-Lead ECG 
 
 
 
Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Abnormal, Not Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Abnormal, Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Not Performed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Heregulin (HRG) 
 
 
 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx x 
xx.x 
SD 
xx.xx 
xx.x  
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
Minimum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
 
 
 
 
Notes: Denominator for percentages is the number of subjects in the Safety Analysis Set    
            The baseline value is defined as the last non-missing value before in al administration of study treatment. 
            [a]  Age in years is calculated using the informed consent date a d the irth date. 
Source Data: adam.adsl; Listing 16.2.4.1, 16.2.4.4.1, 16.2.4.4.2, 16 2 4.4.3, 16.2 4.4.4, 16.2.4.6, 16.2.8.3.2, 16.2.8.3.4, 16.2.8.4.2. 
Programming Note: continue for HRG Low and Overall on the next page    
 
 
Programming note: Present ‘Missing’ as a category if here is at least one subject in a row. 
 
Using the table shell of 15.1.2.1 for following 3 tables: 
Table 15.1.2.2: Demographic and Baseline Characteristics    
Per Protocol Analysis Set 
 
Change first line footnote to: Denominator for percentages is the number of subjects in Per Protocol Analysis Set 
 
Table 15.1.2.3: Demographic and Baseline Characteristics    
Safety Analysis Set 
 
Change first line footnote to: Denominator for percentages is the number of subjects in Safety Analysis Set 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
<Run Type> (Data Cut Date: DDMMMYYYY; Data Extraction Date: DDMMMYYY) 
Page 83 of 190 
Table 15.1.3: Study Drug Exposure  
Safety Analysis Set 
HRG High 
 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
Placebo + cetuximab + 
cisplatin or carboplatin 
Patritumab  
(N=xxx) 
Cetuximab 
 (N=xxx) 
Carboplatin 
 (N=xxx) 
Cisplatin 
 (N=xxx) 
Placebo  
(N=xxx) 
Cetuximab 
 (N=xxx) 
Carboplatin 
 (N=xxx) 
Cisplatin 
 (N=xxx) 
Cumulative Dose Received per Subject 
(mg) [a] 
 
 
 
 
 
 
 
 
       n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx x 
xx.xx 
xx.xx 
xx.xx 
       SD 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx xx  
xx.xxx 
xx.xxx 
xx.xxx 
       Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
x.x 
xx.x 
xx.x 
xx.x 
       Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Cumulative Dose Received per Subject 
(mg/kg) 
 
 
 
 
 
 
 
 
       n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
       SD 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
       Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
       Median 
xx 
xx 
x 
xx 
xx 
xx 
xx 
xx 
       Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Xx 
 
Dose Intensity (mg/kg/cycle/dose) [a] 
 
 
 
 
 
 
 
 
       n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
       SD 
xx.xxx 
xx xx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
       Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
       Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:  For Patritumab, treatment duration (in weeks) is calculated as (date of the last dose – date of the first dose + 21)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 21)/21. 
             For Cetuximab, treatment duration (in weeks) is calculated as (date of the last dose – date of the first dose + 7)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 7)/21. 
             For Carboplatin or Cisplatin, treatment duration (in weeks) is calculated as (date of the last dose – date of the first dose + 21)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 21)/21. 
             [a] Refer to SAP Section 8.3.6 for definitions for Cumulative Dose Received per Subject, Dose Intensity, and Relative Dose Intensity, and Cycle Duration.. 
 
Source Data: adam.adex; Listing 16.2.5.1.1, 16.2.5.1.2, 16.2.5.1.3. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 84 of 190 
Table 15.1.3: Study Drug Exposure  
Safety Analysis Set 
 
Overall 
 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
Placebo + cetuximab + 
cisplatin or carboplatin 
Patritumab  
(N=xxx) 
Cetuximab 
 (N=xxx) 
Carboplatin 
 (N=xxx) 
Cisplatin 
 (N=xxx) 
Placebo  
(N=xxx) 
Cetuximab 
 (N=xxx) 
Carboplatin 
 (N=xxx) 
Cisplatin 
 (N=xxx) 
Relative Dose Intensity (%) [a] 
 
 
 
 
 
 
 
 
       n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
       SD 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx. xx 
xx.xxx 
xx.xxx 
xx.xxx 
       Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx x 
xx.x 
xx.x 
xx.x 
       Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Cycle Duration (Days) 
 
 
 
 
 
 
 
 
       n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Mean 
xx.xx 
xx.xx 
xx.xx 
xx. x 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
       SD 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
       Minimum 
xx.x 
xx.x 
xx.x 
x.x 
xx.x 
xx.x 
xx.x 
xx.x 
       Median 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Xx 
 
Cycles Delayed 
 
 
 
 
 
 
 
 
       n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
       SD 
xx.xxx 
xx.xxx 
xx xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
       Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
       Median 
xx 
x 
xx 
xx 
xx 
xx 
xx 
xx 
       Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:  For Patritumab, treatment duration (in weeks) is calculated as (date of the last dose – date of the first dose + 21)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 21)/21. 
             For Cetuximab, treatment duration (in weeks) is calculated as (date of the last dose – date of the first dose + 7)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 7)/21. 
             For Carboplatin or Cisplatin, treatment duration (in weeks) is calculated as (date of the last dose – date of the first dose + 21)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 21)/21. 
             [a] Refer to SAP Section 8.3.6 for definitions for Cumulative Dose Received per Subject, Dose Intensity, and Relative Dose Intensity, and Cycle Duration.. 
 
Source Data: adam.adex; Listing 16.2.5.1.1, 16.2.5.1.2, 16.2.5.1.3. 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 85 of 190 
Table 15.1.3: Study Drug Exposure  
Safety Analysis Set 
 
Overall 
 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
Placebo + cetuximab + 
cisplatin or carboplatin 
Patritumab  
(N=xxx) 
Cetuximab 
 (N=xxx) 
Carboplatin 
 (N=xxx) 
Cisplatin 
 (N=xxx) 
Placebo  
(N=xxx) 
Cetuximab 
 (N=xxx) 
Carboplatin 
 (N=xxx) 
Cisplatin 
 (N=xxx) 
Cycles Delayed 
 
 
 
 
 
 
 
 
       0 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       >=2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
Dose Reductions 
 
 
 
 
 
 
 
 
       n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
       Mean 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx x 
xx.xx 
xx.xx 
xx.xx 
       SD 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
       Minimum 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
       Median 
xx 
xx 
xx 
x  
xx 
xx 
xx 
xx 
       Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Xx 
 
       0 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
       >=2 
xx (xx.x%) 
xx (xx.x%) 
xx ( x.x%  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:  For Patritumab, treatment duration (in weeks) is calculated as (date of th  last dose – date of the first dose + 21)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 21)/2 . 
             For Cetuximab, treatment duration (in weeks) is calcu ated as (date of the last dose – date of the first dose + 7)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first do
 + 7)/21. 
             For Carboplatin or Cisplatin, treatment duration (in weeks) is calculated as (date of the last dose – date of the first dose + 21)/7. Treatment duration (in cycles)  
             is calculated as (date of the last dose – date of the first dose + 21)/21. 
             [a] Refer to SAP Section 8.3.6 for definitions for Cumulative Dose Received per Subject, Dose Intensity, and Relative Dose Intensity, and Cycle Duration.. 
 
Source Data: adam.adex; Listing 16.2.5.1.1, 16.2.5.1.2, 16.2.5.1.3. 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 86 of 190 
 
Table 15.1.4.1: Prior Medications by ATC Class and Preferred Term 
Safety Analysis Set 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
(N=xxx) 
 
 
 
 
Subjects with any Prior Medications 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
ATC 2 Class x 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term 1 
xx (xx.x) 
xx ( x.x) 
xx (xx.x) 
  Preferred Term 2 
xx (xx.x) 
xx (xx x) 
xx (xx.x) 
  Preferred Term 3 
xx (xx.x) 
x  (xx.x) 
xx (xx.x) 
  Preferred Term n 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
ATC 2 Class y 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term n 
xx (xx x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
ATC 2 Class z 
xx ( x.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term 1 
xx (xx x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Preferred Term n 
x (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Notes: Denominator for percentages is the number of subjects in the Safety Analysis Set. 
           Medications taken prior to the first dose of study medication will be classified as prior medications. 
           Subjects may have more than one medication per ATC classification and preferred term.  At each level of subject summarization, a subject was counted once if he/she reported 
one or more medications. 
           Medications were coded using the WHO Drug Dictionary (Version XXX). 
 
Source Data: adam.adcm; Listing 16.2.4.5 
Programming Note: continue for HRG Low and Overall on the next page  
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 87 of 190 
Use tables shell of 15.1.6.1 to generate 15.16.2: 
 
Table 15.1.4.2: Concomitant Medications by ATC Class and Preferred Term 
Safety Analysis Set 
Programming note:  Replace the second sentence with “Medications taken on or after the first dose of study medication will be classified as concomitant 
medications”. 
First row should state ‘Subjects with any Concomitant Medications’ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 88 of 190 
 
Table 15.2.1.1:  Analysis of Progression Free Survival (PFS) 
Full Analysis Set 
 
HRG High 
Statistics 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
 
 
 
 
 
Subject (%) with Events 
xx (xx.x%) 
xx (xx.x%) 
 
Subject (%) without Events (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
[xx.x; xx.x] 
[xx x; xx.x] 
 
 
 
 
 
Stratified Log-rank p-value [b] 
 
 
0.xxxx 
Log-rank p-value (Unstratified) [c] 
 
 
0.xxxx 
 
 
 
 
Stratified Cox Regression Analysis [b] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
Unstratified Cox Regression Analysis [c] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
 
 
 
 
PFS Rate at 3 Months [d] 
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 6 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 9 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 12 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Notes: PFS is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever comes first. See the 
SAP for the handling of censored cases. 
[a] Median PFS is from Kaplan-Meier analysis. CI for median was computed using the Brookmeyer-Crowley method. 
[b] Stratified log-rank test adjusted for stratification factors: HRG (high vs low; overall only) and HPV (positive vs other) at randomization. 
[c] Log-rank test did not adjust for stratification factors.  
[d] Estimate and CI for PFS rate at the specified timepoint are from Kaplan-Meier analysis. 
 
Source Data: adam.adtte; Listing 16.2.6.1 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 89 of 190 
 
 
Programming note: If insufficient #’s of subject progress then certain proportions are not estimable and the estimate and corresponding confidence interval will be 
omitted.   
 
Use table shell of 15.2.1.1 to generate following tables: 
 
Table 15.2.1.2: Analysis of Progression Free Survival (PFS) 
Per Protocol Analysis Set 
 
 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.2.1.3:  Subgroup Analysis of Progression Free Survival (PFS) 
Full Analysis Set 
 
Overall 
Subgroup/ 
   Statistic 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
 
 
 
 
 
Age  
 
 
 
  <65 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
       Hazard Ratio (relative to Placebo)[b]  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
  >=65 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
       Hazard Ratio (relative to Placebo)[b]  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
 
 
 
 
Sex 
 
 
 
  Female 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
x.x; xx.x] 
[xx.x; xx.x] 
 
       Hazard Ratio (relative to Placebo)[b]  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
  Male 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
       Hazard Ratio (relative to Placebo)[b]  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
 
 
 
 
Notes: PFS is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever comes first. See the 
SAP for the handling of censored cases. 
[a] Median PFS is from Kaplan-Meier analysis. CI for median was computed using the Brookmeyer-Crowley method. 
[b] Log-rank test did not adjust for stratification factors.  
 
Source Data: adam.adtte; Listing 16.2.6.1 
Programming note: Continue for subgroups in Section 8.2.4.2 of SAP. 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.2.1.4:  Analysis of Progression Free Survival (PFS) for Different HRG Cutoffs 
Full Analysis Set 
 
HRG Cutoff: HRG >= XX.XX 
Statistics 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
 
 
 
 
 
Subject (%) with Events 
xx (xx.x%) 
xx (xx.x%) 
 
Subject (%) without Events (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Stratified Cox Regression Analysis [b] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       80% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
Unstratified Cox Regression Analysis [c] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       80% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
 
 
 
 
PFS Rate at 3 Months [d] 
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 6 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 9 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 12 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Notes: PFS is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever 
comes first. See the SAP for the handling of censored cases. 
[a] Median PFS is from Kaplan-Meier analysis. CI for median was computed using the Brookmeyer-Crowley method. 
[b] Stratified Cox PH regression adjusted for stratification factors: HPV (positive vs other) and HRG (high vs. low, only for the FAS) at randomization. 
[c] Cox PH regression did not adjust for stratification factors.  
[d] Estimate and CI for PFS rate at the specified timepoint are from Kaplan-Meier analysis. 
 
Programming note: If insufficient #’s of subject progress then certain proportions are not estimable and the estimate and corresponding confidence interval will be 
omitted.   
Programming Note: continue for different HRG Cutoff 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.2.2.1:  Analysis of Overall Survival (OS) 
Full Analysis Set 
 
HRG High 
Statistics 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
 
 
 
 
 
Subject (%) with Events 
xx (xx.x%) 
xx (xx.x%) 
 
Subject (%) without Events (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Stratified Log-rank p-value [b] 
 
 
0.xxxx 
Log-rank p-value (Unstratified) [c] 
 
 
0.xxxx 
 
 
 
 
Stratified Cox Regression Analysis [b] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
Unstratified Cox Regression Analysis [c] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       p-value for hazard ratio equal to one                                     
 
 
0.xxxx 
 
 
 
 
PFS Rate at 3 Months [d] 
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 6 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 9 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 12 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Notes: PFS is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever comes first. See the 
SAP for the handling of censored cases. 
[a] OS is defined as the time from the date of randomization to death due to any cause. 
[b] Stratified log-rank test adjusted for stratification factors: HPV (positive vs other) at randomization. 
[c] Log-rank test did not adjust for stratification factors.  
[d] Estimate and CI for OS rate at the specified timepoint are from Kaplan-Meier analysis. 
 
Source Data: adam.adtte; Listing 16.2.6.1 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 93 of 190 
 
 
 
Use table shell of 15.2.2.1 to generate following tables: 
 
Table 15.2.2.2 
Analysis of Overall Survival (OS)  
Per Protocol Analysis Set 
 
Change the first line of footnote to: OS is defined as the time from the date of randomization to death due to any cause. 
Change the PFS in table and footnotes to OS. 
 
Use table shell of 15.2.1.3 to generate following tables: 
 
Table 15.2.1.3:  Subgroup Analysis of Overall Surviva  (OS) 
Full Analysis Set 
 
Change the first line of footnote to: OS is defined as the time from the date of randomization to death due to any cause. 
Change the PFS in table and footnotes to OS. 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 94 of 190 
 
Table 15.2.2.3:  Analysis of Overall Survival (OS) for Different HRG Cutoffs 
Full Analysis Set 
 
HRG Cutoff: HRG <= XX.XX 
Statistics 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
 
 
 
 
 
Subject (%) with Events 
xx (xx.x%) 
xx (xx.x%) 
 
Subject (%) without Events (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Median PFS (months) [a] 
xx.x 
xx.x 
 
95% CI 
[xx.x; xx.x] 
[xx x; xx.x] 
 
 
 
 
 
Stratified Cox Regression Analysis [b] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       80% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
Unstratified Cox Regression Analysis [c] 
 
 
 
       Hazard Ratio (relative to Placebo)  
 
 
x.xxxx 
       95% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
       80% CI for Hazard Ratio 
 
 
[x.xxxx, x.xxxx] 
 
 
 
 
PFS Rate at 3 Months [d] 
xx.x% 
xx.x% 
 
95% CI 
x.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 6 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 9 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
PFS Rate at 12 Months  
xx.x% 
xx.x% 
 
95% CI 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Notes: PFS is defined as the time from the date of randomization to the date of the first radiographic disease progression or death due to any cause, whichever 
comes first. See the SAP for the handling of censored cases. 
[a] OS is defined as the time from the date of randomization to death due to any cause.. 
[b] Stratified Cox PH regression adjusted for stratification factors: HPV (positive vs other) at randomization. 
[c] Cox PH regression did not adjust for stratification factors.  
[d] Estimate and CI for OS rate at the specified timepoint are from Kaplan-Meier analysis. 
 
Programming note: If insufficient #’s of subject progress then certain proportions are not estimable and the estimate and corresponding confidence interval will be 
omitted.   
Programming Note: continue for different HRG Cutoff 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 95 of 190 
 
Table 15.2.3.1: Best Overall Tumor Response and Objective Response Rate (ORR) 
Full Analysis Set 
HRG High 
Subjects with measurable disease 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
 
 
 
 
Subject with Measurable Disease at Baseline, n 
(%) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
Objective Response (CR, PR) 
 
 
 
  n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
  95% CI [a] 
[xx.x; xx.x] 
[xx. ; xx x] 
 
  Between-arm difference (relative to placebo) 
 
 
 
      95% CI [b] 
 
 
[xx.x; xx.x] 
      80% CI [b] 
 
 
[xx.x; xx.x] 
 
 
 
 
Complete Response (CR) 
 
 
 
  n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
  95% CI [a] 
[xx.x; x x] 
[xx.x; xx.x] 
 
 
 
 
 
Partial Response (PR) 
 
 
 
  n (%) 
xx (xx.x
) 
xx (xx.x%) 
 
  95% CI [a] 
[xx.x; xx.x] 
[xx.x; xx.x] 
  95% CI [a] 
 
 
 
 
Stable Disease (SD) 
 
 
 
  n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
  95% CI [a] 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Progressive Disease (PD) 
 
 
 
  n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
  95% CI [a] 
[xx.x; xx.x] 
[xx.x; xx.x] 
 
 
 
 
 
Inevaluable 
 
 
 
  n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Note:   Denominator for percentages is the number of subjects with measurable disease.  
The best overall response is the best response (in the order of CR, PR, SD, and PD) among all overall responses recorded from the start of treatment 
until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response of 
Inevaluable captured in the CRF, the best overall response is classified as Inevaluable. 
[a] Based on Wilson’s score method for single proportion with continuity correction. 
[b] Based on Wilson’s score method for the difference of two proportions with continuity correction. 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 96 of 190 
 
Source Data: adam.adrs; Appendices 16.2.6.1.3, 16.2.6.3 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
The following table follows Table 15.2.3.1: 
 
 
 
 
 
Table 15.2.3.2 
Best Overall Tumor Response and Objective Response Rate (ORR) 
Per Protocol Analysis Set 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Programming Note: continue for different HRG Cutoff. 
 
Table 15.2.4: Duration of Objective Response/Stable Disease and Time to Response/Disease Progression in Months  
Full Analysis Set 
 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Duration of Objective Response [a] 
 
 
 
Subjects with Objective Response 
xx 
xx 
 
n. (%) subjects with radiographic disease progression 
xx (xx.x%) 
xx (xx.x%) 
 
Median 
xx.xx 
xx.xx 
 
95% CI for Median 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
 
80% CI for Median 
[xx.xx, xx xx] 
[xx.xx, xx.xx] 
 
1st Quantile 
xx xx 
xx.xx 
 
3rd Quantile 
xx.xx 
xx.xx 
 
Min, Max 
xx.x  xx.x* 
xx.x*, xx.x 
 
 
 
 
 
Duration of Stable Disease [a] 
 
 
 
Subjects with Stable Disease 
xx 
xx 
 
n  (%) subjects with radiographic disease progression 
xx (xx.x%) 
xx (xx.x%) 
 
Median 
xx.xx 
xx.xx 
 
95% CI for Median 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
 
80% CI for Median 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
 
1st Quantile 
xx.xx 
xx.xx 
 
3rd Quantile 
xx.xx 
xx.xx 
 
Min, Max 
xx.x, xx.x* 
xx.x*, xx.x 
 
 
 
 
 
Notes:  
Duration of objective response is defined for subjects with CR/PR as the time from the date of the first documentation of objective response (CR or PR) to the date 
of the first documentation of progressive disease.  
Duration of SD is defined for subjects whose best response is SD as the time from the randomization date to the date of the first documentation of progressive 
disease.   
Time to response is defined as the time from the randomization date to the date of the first documentation of objective response (CR or PR).  
Time to disease progression is defined as the time from the randomization date to the date of first objective documentation of disease progression.  
See the SAP for the handling of censored cases.  
[a] Median, 1st and 3rd quantiles are from Kaplan-Meier Estimate. CI for median was computed using the Brookmeyer-Crowley method. Minimum and maximum 
include the censored observations where using “+” after value indicates censoring. 
 
Source Data: adam.adtte; Listing 16.2.6.2, 16.2.6.3 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.2.4.: Duration of Objective Response/Stable Disease and Time to Response/Disease Progression in Weeks 
Full Analysis Set 
 
HRG High 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Time to Response [a] 
 
 
 
n. (%) subjects with objective response 
xx (xx.x%) 
xx (xx.x%) 
 
Median 
xx.xx 
xx.xx 
 
95% CI for Median 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
 
80% CI for Median 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
 
1st Quantile 
xx.xx 
xx.xx 
 
3rd Quantile 
xx.xx 
xx.xx 
 
Min, Max 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
 
 
Time to Disease Progression [a] 
 
 
 
n. (%) subjects with radiographic disease progression 
xx ( x.x%) 
xx (xx.x%) 
 
Median 
xx.xx 
xx.xx 
 
95% CI for Median 
[x xx, xx.xx] 
[xx.xx, xx.xx] 
 
80% CI for Median 
[xx.xx, xx.xx] 
[xx.xx, xx.xx] 
 
1st Quantile 
xx.xx 
xx.xx 
 
3rd Quantile 
xx.xx 
xx.xx 
 
Min, Max 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
 
 
 
 
Notes 
Duration of objective response is defined for subjects with CR/PR as the time from the date of the first documentation of objective response (CR or PR) to the date 
of the first documentation of progressive disease.  
Duration of SD is defined for subjects whose best response is SD as the time from the randomization date to the date of the first documentation of progressive 
disease.   
Time to response is defined as the time from the randomization date to the date of the first documentation of objective response (CR or PR).  
Time to disease progression is defined as the time from the randomization date to the date of first objective documentation of disease progression.  
See the SAP for the handling of censored cases. 
[a] Median, 1st and 3rd quantiles are from Kaplan-Meier Estimate. CI for median was computed using the Brookmeyer-Crowley method. Minimum and maximum 
include the censored observations where using “+” after value indicates censoring. 
 
Source Data: adam.adtte; Listing 16.2.6.2, 16.2.6.3 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 99 of 190 
 
Table 15.2.5: Summary of Change and the Percent Change from Baseline in the Sum of Longest Diameters (mm) of Target Lesions 
Full Analysis Set 
 
HRG High 
 
 
 
 
Patritumab + cetuximab +  
cisplatin or carboplatin 
(N-xxx)
 
Placebo + cetuximab + 
 cisplatin or carboplatin  
 (N=xxx) 
 
Visit 
Result 
(mm) 
Change 
(mm) 
% Change 
Result 
Change 
% Change 
Baseline 
 
 
 
 
 
 
     n 
xx 
 
 
xx 
 
 
     Mean 
xx.x 
 
 
xx.x 
 
 
     SD 
xx.xx 
 
 
xx.xx 
 
 
     Median 
xx.x 
 
 
xx.x 
 
 
     Minimum 
xx. 
 
 
xx. 
 
 
     Maximum 
xx 
 
 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week X 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.  
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx. 
xx  
xx. 
xx. 
xx. 
xx. 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. Time points with data from fewer than 5 subjects 
overall are not summarized.  Repeated or unscheduled tests are not summarized for each scheduled visit, but are included for summaries of minimum 
post -baseline values. 
Source Data: adam.adrs; Listing 16.2.6.1.3 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.2.5: Summary of Change and the Percent Change from Baseline in the Sum of Longest Diameters (mm) of Target Lesions 
Full Analysis Set 
 
HRG High 
 
 
 
                          Patritumab + cetuximab +  
cisplatin or carboplatin 
(N-xxx)
 
Placebo + cetuximab + 
 cisplatin or carboplatin  
 (N=xxx) 
 
Visit 
Result 
(mm) 
Change 
(mm) 
% Change 
Result 
Change 
% Change 
Week N 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx. 
xx. 
xx  
xx. 
xx. 
xx. 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum Post-baseline Value 
(Nadir) 
 
 
 
 
 
 
     n 
xx 
 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx. 
xx. 
xx. 
xx. 
xx. 
xx. 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. Time points with data from fewer than 5 subjects 
overall are not summarized.  Repeated or unscheduled tests are not summarized for each scheduled visit, but are included for summaries of minimum 
post-baseline values. 
Source Data: adam.adrs; Listing 16.2.6.1.3 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 101 of 190 
Table 15.3.1.1:  Overview of Number (%) of Subjects Reporting Treatment-Emergent Adverse Events 
Safety Analysis Set 
HRG High 
 
     Patritumab+ cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
      Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
 
 
 
 
Treatment-Emergent Adverse Events (TEAE) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Worst CTCAE Grade  
 
 
 
    5       
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    >=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Missing 
 
 
 
     
 
 
 
TEAE Related to Patritumab 
xx (xx.x%) 
xx ( x x%) 
xx (xx.x%) 
  Worst CTCAE Grade  
 
 
 
    5    
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
….. 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    >=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
TEAE Related to Cetuximab 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
  Worst CTCAE Grade  
 
 
 
    5        
xx (xx.x%  
xx (xx.x%) 
xx (xx.x%) 
    4 
xx (x x%) 
xx (xx.x%) 
xx (xx.x%) 
    ... 
 
 
 
    >=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
TEAE Related to Cisplatin 
 
 
 
 Worst CTCAE Grade   
 
 
 
  … 
 
 
 
 
 
 
 
TEAE Related to Carboplatin 
 
 
 
 Worst CTCAE Grade  
 
 
 
  … 
 
 
 
Notes: In the presence of a subject who has both missing and non-missing CTCAE grades for adverse events, the missing CTCAE grade of the adverse  
           event is treated as the lowest severity grade.  
           Adverse events were coded using the MedDRA dictionary, Version XXX. 
 
Source Data: adam.adae; Listing 16.2.7.2. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 102 of 190 
Table 15.3.1.1:  Overview of Number (%) of Subjects Reporting Treatment-Emergent Adverse Events 
Safety Analysis Set 
 
HRG High 
 
     Patritumab + cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
         Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
 
 
 
 
Treatment-Emergent SAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Worst CTCAE Grade  
 
 
 
    5 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    4 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
    3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    2 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
    1 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
    >=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Missing 
 
 
 
     
 
 
 
Treatment-Emergent SAE Related to Patritumab 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Worst CTCAE Grade  
 
 
 
    5 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    >=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    ... 
 
 
 
    Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Treatment-Emergent SAE Related to Cetuximab 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
  Worst CTCAE Grade  
 
 
 
    5 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    4 
xx ( x.x%) 
xx (xx.x%) 
xx (xx.x%) 
    ... 
 
 
 
    >=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Treatment-Emergent SAE Related to Cisplatin 
 
 
 
 Worst CTCAE Grade  
 
 
 
  … 
 
 
 
 
 
 
 
Treatment-Emergent SAE Related to Carboplatin 
 
 
 
 Worst CTCAE Grade 
 
 
 
  … 
 
 
 
Notes: In the presence of a subject who has both missing and non-missing CTCAE grades for adverse events, the missing CTCAE grade of the adverse  
           event is treated as the lowest severity grade.  
           Adverse events were coded using the MedDRA dictionary, Version XXX. 
           Source Data: adam.adae; Listing 16.2.7.2. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 103 of 190 
Table 15.3.1.1:  Overview of Number (%) of Subjects Reporting Treatment-Emergent Adverse Events 
Safety Analysis Set 
 
HRG High 
 
     Patritumab+ cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
      Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
 
 
 
 
Discontinued Patritumab Due to TEAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
Discontinued Cetuximab Due to TEAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
Discontinued Cisplatin Due to TEAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   
 
 
 
Discontinued Carboplatin Due to TEAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
TEAE leading to Patritumab Interruption 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
TEAE leading to Patritumab Interruptio Related to Patritumab  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
TEAE leading to Patritumab Dose Reduction  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
TEAE leading to Patritumab Dose Reduction Related to Patritumab  
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Discontinued Patritumab Due to TEAE  
x (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Related to Patritumab  
 
 
 
Discontinued Cetuximab Due to TEAE  
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
   Related to Cetuximab  
 
 
 
Discontinued Cisplatin Due to TEAE  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Related to Cisplatin  
 
 
 
Discontinued Carboplatin Due to TEAE  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Related to Carboplatin  
 
 
 
 
  
 
 
 
Discontinued Patritumab Due to Treatment Emergent SAE  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Discontinued Cetuximab Due to Treatment Emergent SAE                    
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Discontinued Cisplatin Due to Treatment Emergent SAE                          
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Discontinued Carboplatin Due to Treatment Emergent SAE                      
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Notes: In the presence of a subject who has both missing and non-missing CTCAE grades for adverse events, the missing CTCAE grade of the adverse  
           event is treated as the lowest severity grade.  
           Adverse events were coded using the MedDRA dictionary, Version XXX. 
Source Data: adam.adae; Listing 16.2.7.2. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 104 of 190 
Table 15.3.1.1:  Overview of Number (%) of Subjects Reporting Treatment-Emergent Adverse Events 
Safety Analysis Set 
 
HRG High 
 
     Patritumab+ cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
      Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
 
Total 
 (N=xxx) 
 
 
 
 
Discontinued Patritumab Due to Treatment Emergent    
  SAE Related to Patritumab 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Discontinued Cetuximab Due to Treatment Emergent  
  SAE Related to Cetuximab                        
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Discontinued Cisplatin Due to Treatment Emergent  
  SAE Related to Cisplatin                        
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Discontinued Carboplatin Due to Treatment Emergent 
SAE Related to Carboplatin                      
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
TEAE leading to Death  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
TEAE leading to Death Related to Patritumab 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   
 
 
 
TEAE leading to Death Related to Cetuximab 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
TEAE leading to Death Related to Cisplatin 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
TEAE leading to Death Related to Carboplatin 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
Notes: In the presence of a subject who has both missing and non-m ssing CTCAE grades for adverse events, the missing CTCAE grade of the adverse  
           event is treated as the lowest severity grade.  
           Adverse events were coded using the MedDRA dict onar  Versio  XXX. 
 
Source Data: adam.adae; Listing 16.2.7.2. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 105 of 190 
Table 15.3.1.2:  Number and Percentage of Subjects with Treatment-emergent Adverse Events Summarized by Worst CTCAE Grade, 
System Organ Class, and Preferred Term 
Safety Analysis Set 
 
HRG High 
System Organ Class 
Preferred Term 
Worst CTCAE 
Grade 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
Placebo + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
 
Total 
 (N=xxx) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
Subjects with any TEAEs 
 
Any Grade 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
5 
xx (xx.x%) 
xx (x x%) 
xx (xx.x%) 
 
 
4 
xx (xx.x%) 
xx (xx %) 
xx (xx.x%) 
 
 
3 
xx (xx.x%) 
xx (xx.x
) 
xx (xx.x%) 
 
 
2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
1 
xx (xx.x%) 
xx (x x%) 
xx (xx.x%) 
 
 
>=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
System Organ Class #1 
Any Preferred Term 
Any Grade 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
5 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
3 
xx (x x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
2 
xx (xx. %) 
xx (xx.x%) 
xx (xx.x%) 
 
 
1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Missing 
x (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Notes:    In the presence of a subject who has both missing and non-mis ing CTCAE grades for adverse events with the same preferred term, the missing  
              CTCAE grade of the adverse event is treated as the lowes  sever y grade.  
              Subjects may have more than one event per system organ class and preferred term. At each level of subject summarization, a subject was counted once if he/she reported    
              one or more adverse events. 
              Adverse events were coded using the MedDRA dictionary, Version XXX. 
Source Data: adam.adae; Listing 16.2.7.2. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 106 of 190 
Table 15.3.1.2:  Number and Percentage of Subjects with Treatment-emergent Adverse Events Summarized by Worst CTCAE Grade, 
System Organ Class, and Preferred Term 
Safety Analysis Set 
 
HRG High 
System Organ Class 
Preferred Term 
Worst CTCAE 
Grade 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
Placebo + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
 
Total 
 (N=xxx) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
System Organ Class #1 
Preferred Term #1 
Any Grade 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
5 
xx (xx.x%) 
xx (x x%) 
xx (xx.x%) 
 
 
4 
xx (xx.x%) 
xx (xx. %) 
xx (xx.x%) 
 
 
3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
2 
xx (xx.x%) 
xx ( x.x%) 
xx (xx.x%) 
 
 
1 
xx (xx.x%) 
x  (xx x%) 
xx (xx.x%) 
 
 
>=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
System Organ Class #1 
Preferred Term N 
Any Grade 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
5 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
3 
xx (x x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
1 
xx ( x.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
>=3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
Missing 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
System Organ Class N 
Any   
Preferred Term 
 
 
 
 
 
Etc. 
 
 
 
 
 
 
 
 
 
 
Notes:    In the presence of a subject who has both missing and non-missing CTCAE grades for adverse events with the same preferred term, the missing  
              CTCAE grade of the adverse event is treated as the lowest severity grade.  
              Subjects may have more than one event per system organ class and preferred term. At each level of subject summarization, a subject was counted once if he/she    
              reported one or more adverse events. 
              Adverse events were coded using the MedDRA dictionary, Version XXX. 
Source Data: adam.adae; Listing 16.2.7.2. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 107 of 190 
 
The following table follows 15.3.1.2: 
 
 
Table 15.3.1.3:  Number and Percentage of Subjects with Treatment-emergent Serious Adverse Events Summarized  
by Worst CTCAE Grade, System Organ Class, and Preferred Term  
Safety Analysis Set 
 
 
First Row: Subjects with any treatment emergent SAEs 
 
 
Table 15.3.1.4:  Number and Percentage of Subjects with Treatment-emergent Adverse Events Related to Patritumab/Placebo Summarized  
by Worst CTCAE Grade, System Organ Class, and Preferred Term 
Safety Analysis Set 
First Row: Subjects with any TEAEs related to Patritumab 
 
 
Table 15.3.1.5:  Number and Percentage of Subjects with Treatment-emerg
t Adverse Events Related to Cetuximab Summarized  
by Worst CTCAE Grade, System Organ Class, and Preferred Term 
Safety Analysis Set 
 
First Row: Subjects with any TEAEs related to Cetuximab 
 
 
Table 15.3.1.6:  Number and Percentage of Subjects with reatment-emergent Adverse Events Related to Cisplatin/Carboplatin Summarized  
by Worst CTCAE Grade  System Organ Class, and Preferred Term 
Safety Analysis Set 
 
First Row: Subjects with any TEAEs related to Cisplatin/ Carbop atin 
 
 
 
Table 15.3.1.7:  Number and Percentage of Subjects with Treatment-emergent Serious Adverse Events Related to Patritumab/Placebo Summarized  
by Worst CTCAE Grade, System Organ Class, and Preferred Term 
Safety Analysis Set 
 
First Row: Subjects with any treatment emergent SAEs related to Patritumab 
 
 
Table 15.3.1.8:  Number and Percentage of Subjects with Treatment-emergent Serious Adverse Events Related to Cetuximab Summarized  
by Worst CTCAE Grade, System Organ Class, and Preferred Term 
Safety Analysis Set 
First Row: Subjects with any treatment emergent SAEs related to Cetuximab 
 
 
Table 15.3.1.9:  Number and Percentage of Subjects with Treatment-emergent Serious Adverse Events Related to Cisplatin/Carboplatin Summarized  
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 108 of 190 
by Worst CTCAE Grade, System Organ Class, and Preferred Term 
Safety Analysis Set 
 
First Row: Subjects with any treatment emergent SAEs related to Cisplatin/Carboplatin 
 
 
Table 15.3.1.10: 
Number and Percentage of Subjects with Adverse Events of Interest by Worst CTCAE Grade, System Organ Class, and Preferred Term 
Safety Analysis Set 
 
 
First Row: Subjects with any adverse events of interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 109 of 190 
Table 15.3.4.1: Summary of Results and Change from Baseline in Laboratory Tests – Hematology 
Safety Analysis Set 
 
HRG High 
 
 
 
Lab Test (units) 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Placebo + cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Total 
____(N=xxx)_____ 
   Visit 
 Result 
Change  
 Result 
Change  
 Result 
Change  
Lab Test #1 (SI unit) 
 
 
 
 
 
 
   Baseline 
 
 
 
 
 
 
     n 
xx 
 
xx 
 
xx 
 
     Mean 
xx.x 
 
xx.x 
 
xx.x 
 
     SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
     Median 
xx.x 
 
xx.x 
 
xx.x 
 
     Minimum 
xx 
 
xx 
 
xx 
 
     Maximum 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
   Cycle X Day X 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
xx 
x 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
Note: The baseline value is defined as the last non-missing value before initia  administration of study treatment. Repeated or unscheduled tests are not summarized for each 
scheduled visit, but are included for summaries of last observation on trea
en  maximum and minimum post-baseline values. Last observation on treatment is defined as the last 
non-missing value on or prior to end of treatment duration + 7. Perce tages are b sed on the number of subjects meeting the defined criteria (m); the number of subjects with non-
missing observations for the specified visit (n) is the denominator. 
Source Data: adam.adlb; Listing 16.2.8.1.1 
 
Programming Note: do not summarize Cycle 1 Day 1. Do not summarize coagulation parameters.  
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Daiichi Sankyo Pharma Development                                                                                                            Page x of y 
Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 110 of 190 
Table 15.3.4.1: Summary of Results and Change from Baseline in Laboratory Tests – Hematology 
Safety Analysis Set 
 
HRG High 
 
 
 
Lab Test (units) 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Placebo + cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Total 
____(N=xxx)_____ 
   Visit 
 Result 
Change  
 Result 
Change  
 Result 
Change  
Lab Test #1 (SI unit) 
 
 
 
 
 
 
End of Treatment 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
   Last Observation on Treatment 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
     Maximum Post-Baseline Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Minimum Post-Baseline Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab Test N…. 
 
 
 
 
 
 
Note: The baseline value is defined as the last non-missing value before initial administration of study treatment. Repeated or unscheduled tests are not summarized for each 
scheduled visit, but are included for summaries of last observation on treatment, maximum and minimum post-baseline values. Last observation on treatment is defined as the last 
non-missing value on or prior to end of treatment duration + 7. Percentages are based on the number of subjects meeting the defined criteria (m); the number of subjects with non-
missing observations for the specified visit (n) is the denominator. 
Source Data: adam.adlb; Listing 16.2.8.1.1 
 
Programming Note: do not summarize Cycle 1 Day 1. Do not summarize coagulation parameters.  
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
 
 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 111 of 190 
 
 
The following table follows Table 15.3.4.1: 
 
Table 15.3.4.2: Summary of Results and Change from Baseline in Laboratory Tests - Chemistry 
Safety Analysis Set 
Source Data: adam.adlb; Listing 16.2.8.1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 112 of 190 
Table 15.3.4.3: Shift Table of CTCAE Grade in Laboratory Tests – Hematology  
Safety Analysis Set 
 
HRG High 
 
 
Worst Post-baseline CTCAE Grade  
Condition (Unit) 
  Treatment 
Baseline 
CTCAE Grade 
< 1 
n    (%) 
1 
n    (%) 
2 
n    (%) 
3 
n    (%) 
4 
n    (%) 
3 or 4 
n    (%) 
Total 
n    (%) 
Missing 
n    
 
 
 
 
 
 
 
 
 
 
Condition #1  
 
 
 
 
 
 
 
 
 
   Patritumab+ cetuximab + 
   cisplatin or carboplatin 
   (n=xxx) 
< 1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
1  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
2  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
x  (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
3  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx xx x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
4  
xx (xx.x%) 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
3 or 4  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Total  
xx (xx.x%) 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Missing 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
   Placebo + cetuximab + 
   cisplatin or carboplatin  
   (n=xxx) 
< 1 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
1  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
2  
xx (xx.x%) 
x (x .x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
3  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
4  
xx (xx. %) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
3 or 4  
x  (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Total  
xx xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx 
 
Missing 
x  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
Condition #2 . . . etc. 
 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. 
             For each condition, percentages are based on the number of subjects in the Safety Analysis Set for each cohort with a baseline and at least one post-baseline assessment 
(that is, n in the first column). Subjects classified as missing have a missing test result. 
  Source Data: adam.ad b; Listing 16.2.8.1.1 
  
Programming note: do not summarize coagulation parameters. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 113 of 190 
 
The following table follows 15.3.4.3: 
 
Table 15.3.4.4: Shift Table of CTCAE Grade in Laboratory Tests - Chemistry 
Safety Analysis Set 
 
 
Source Data: adam.adlb; Listing 16.2.8.1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.3.4.5: Number and Percentage of Subjects with Liver Enzymes (ALT, AST) and Total Bilirubin (TBL) Elevation  
Safety Analysis Set 
 
HRG High 
Category 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
Placebo + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
Total 
(N=xxx) 
Subjects with post-baseline AST    
 
 
 
     
    AST >= 3 x ULN 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
    AST >= 5 x ULN  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    AST >= 8 x ULN  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    AST >= 10 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    AST >= 20 x ULN  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Subjects with post-baseline ALT    
 
 
 
     
    ALT >= 3 x ULN 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
    ALT >= 5 x ULN  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    ALT >= 8 x ULN  
xx (xx x) 
xx (xx.x) 
xx (xx.x) 
    ALT >= 10 x ULN 
x (xx.x) 
xx (xx.x) 
xx (xx.x) 
    ALT >= 20 x ULN  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Subjects with post-baseline AST or ALT   
 
 
 
     
    AST >= 3 x ULN or ALT >= 3 x ULN 
 
xx (xx.x) 
 
xx (xx.x) 
 
xx (xx.x) 
    AST >= 5 x ULN or ALT >= 5 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    AST >= 8 x ULN or ALT >= 8 x ULN 
             xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    AST >= 10 x ULN or ALT >= 10 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    AST >= 20 x ULN or ALT >= 20 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 TBL  >= 2 x ULN 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Concurent TBL  >= 2 x ULN and AST >= 3 x ULN      
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Concurent TBL  >= 2 x ULN and ALT >= 3 x ULN      
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Concurent TBL  >= 2 x ULN and AST   or ALT >= 3 x ULN   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Concurent TBL  >= 2 x ULN and AST or ALT >= 3 x ULN and ALP >= 2 x ULN   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Concurent TBL  >= 2 x ULN and AST or ALT >= 3 x ULN and ALP <= 2 x ULN   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
  Notes: ULN = Upper limit of normal ranges. 
      Concurent is defined as at least one case of post-dose TBL >= 2 x ULN occurred between the first incidence date and 30 days after the last     
      incidence date of the corresponding liver enzyme(s) >= 3 x ULN 
Source Data: adam.adlb; Listing 16.2.8.1.1 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.3.5:  Summary of Vital Signs and Change from Baseline  
Safety Analysis Set 
 
HRG High 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. Repeated or unscheduled tests are not summarized for each 
scheduled visit, but are included for summaries of last observation on treatment, maximum and minimum post-baseline values. The End of Treatment value is based on the CRF visit. 
Last observation on treatment is defined as the last non-missing value on or prior to end of treatment duration + 7. 
Source Data: adam.advs; Listing 16.2.8.3.1. 
Programming note:  continue table for Diastolic Blood Pressure, Pulse Rate,Temperature and Weight 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Placebo + cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Total 
____(N=xxx)_____ 
 
Vital Sign (units) 
   Visit 
 Result 
Change  
 Result 
Change  
Result 
Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Systolic Blood Pressure (mmHg) 
 
 
 
 
 
 
   Baseline 
 
 
 
 
 
 
     n 
xx 
 
xx 
 
xx 
 
     Mean 
xx.x 
 
xx.x 
 
xx.x 
 
     SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
     Median 
xx.x 
 
xx.x 
 
xx.x 
 
     Minimum 
xx 
 
xx 
 
xx 
 
     Maximum 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
   Cycle 1 Day 1 
 
 
 
 
 
 
    Pre-infusion 
 
 
 
 
 
 
     n 
xx 
 
xx 
 
xx 
 
     Mean 
xx.x 
 
xx  
 
xx.x 
 
     SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
     Median 
xx.x 
 
x x 
 
xx.x 
 
     Minimum 
xx 
 
xx 
 
xx 
 
     Maximum 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
    Post-infusion 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     … 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Cycle N Day N 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.3.5:  Summary of Vital Signs and Change from Baseline  
Safety Analysis Set 
 
HRG High 
 
 
 
Vital Sign (units) 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Placebo + cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Total 
____(N=xxx)_____ 
   Visit 
 Result 
Change  
 Result 
Change  
 Result 
Change  
Systolic Blood Pressure (mm Hg) 
 
 
 
 
 
 
   End of Treatment 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
x.xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx x 
xx.x 
     Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
   Last Observation on Treatment  
 
 
 
 
 
 
     n 
xx 
xx 
xx 
x 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx.x 
xx x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
   Maximum Post-baseline Value 
 
 
 
 
 
 
     N 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
x.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx  
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
   Minimum Post-baseline Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab Test N (SI unit) 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. Repeated or unscheduled tests are not summarized for each 
scheduled visit, but are included for summaries of last observation on treatment, maximum and minimum post-baseline values. The End of Treatment value is based on the CRF visit. 
Last observation on treatment is defined as the last non-missing value on or prior to end of treatment duration + 7.   
Source Data: adam.advs; Listing 16.2.8.3.1. 
Programming note:  continue table for Diastolic Blood Pressure, Pulse Rate, Respiratory Rate, Body Temperature and Weight 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Page 117 of 190 
 
Table 15.3.6.1:  Summary of 12-Lead ECG and Change from Baseline  
Safety Analysis Set 
 
HRG High 
 
 
 
 
Parameter (units) 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Placebo + cetuximab + 
cisplatin or carboplatin 
____(N=xxx)_____ 
Total 
____(N=xxx)_____ 
   Visit 
Result  
Change  
 Result 
Change  
 Result 
Change  
 
 
 
 
 
 
 
Heart Rate (bpm) 
 
 
 
 
 
 
   Baseline 
 
 
 
 
 
 
     n 
xx 
 
xx 
 
x 
 
     Mean 
xx.x 
 
xx.x 
 
xx.x 
 
     SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
     Median 
xx.x 
 
xx.x 
 
xx.x 
 
     Minimum 
xx 
 
xx 
 
xx 
 
     Maximum 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
   End of Treatment 
 
 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.x  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
x.x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
x  
xx 
xx 
xx 
xx 
     Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. The End of Treatment value is based on the CRF visit 
 
Source Data: adam.adeg; Listing 16.2.8.3.2. 
Programming note: continue with PR interval, RR interval, QRS duration, QT interval, QTcB, and QTcF  
Programming Note: continue for HRG Low and Overall on the next page  
 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.3.6.2: Summary of Subjects Meeting Pre-Specified QT and QTcB/QTcF Criteria  
Safety Analysis Set 
 
HRG High 
Maximum Over All Post- Baseline Evaluations 
Patritumab+ cetuximab +  
cisplatin or carboplatin 
 (N=xxx) 
n (%) 
Placebo + cetuximab + 
 cisplatin or carboplatin  
(N=xxx) 
n (%) 
 Total 
(N=xxx) 
n (%) 
 
 
 
 
Subjects with at least one baseline and one post-
baseline ECG evaluation 
xx 
xx 
xx 
 
 
 
 
QTcB 
 
 
 
    New  > 450 msec 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    New > 480  msec 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    New > 500 msec 
xx (xx.x%) 
xx (x x%) 
xx (xx.x%) 
 
 
 
 
    Change from baseline >30 msec 
xx (xx.x%) 
xx xx.x%) 
xx (xx.x%) 
    Change from baseline > 60 msec 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
QTcF 
 
 
 
    New  > 450 msec 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    New > 480 msec 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
    New > 500 msec 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
    Change from baseline >30 msec 
xx ( x.x%) 
xx (xx.x%) 
xx (xx.x%) 
    Change from baseline > 60 msec 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. Percentages are based on the number of subjects in the    
           Safety Analysis Set for each cohort with at least one baseline and one post-baseline ECG assessment. “New” means the category of the QTc abnormality  
           was not present at baseline and became present at least one post-baseline ECG assessment. 
Source Data: adam.adeg; Listing 16.2.8.3.2. 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.3.7: Shift Table of ECOG Status  
Safety Analysis Set 
 
HRG High 
 
 
Post-Baseline ECOG PS 
Time Point 
  Treatment 
Baseline 
ECOG PS 
0 
n    (%) 
1 
n    (%) 
2 
n    (%) 
3 
n    (%) 
4 
n    (%) 
5 
n    (%) 
Total 
n    (%) 
Missing 
n 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 1 
 
 
 
 
 
 
 
 
 
   Patritumab+ cetuximab + cisplatin  
   or carboplatin (n=xxx) 
0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx  
 
1  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx  
 
Total  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx  
 
Missing 
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
 
 
 
 
 
 
 
 
 
 
   Placebo + cetuximab + cisplatin or  
   Carboplatin (n=xxx) 
0  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx  
 
1  
xx (xx.x%) 
xx (xx.x%) 
xx (xx x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx  
 
Total  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx  
 
Missing 
xx  
xx  
xx  
xx  
xx  
xx  
xx  
xx  
 
 
 
 
 
 
 
 
 
 
Cycle x Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Last Observation on Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum Post-baseline Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minimum Post-baseline Value 
 
 
 
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. For each test, percentages are based   
           on the number of subjects in the Safety Analysis Set for each cohort  with a baseline and at least one post-baseline ECOG assessment (that is, n    
            in the first column).  
            Subjects classified as missing have a missing test result.  
Source Data: adam.adqs; Listing 16.2.8.3.4. 
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Protocol U31278-A-U203                                                                                                  <progname> <run date time> 
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Table 15.3.8: Summary of Left Ventricular Ejection Fraction (LVEF) Value and Change from Baseline 
Safety Analysis Set 
HRG High 
 
 
 
 
Parameter (units) 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
(N=xxx)
 
Placebo + cetuximab + 
cisplatin or carboplatin 
(N=xxx)
 
Total 
(N=xxx)
 
   Visit 
Result  
Change  
 Result 
Change  
 Result 
Change  
 
 
 
 
 
 
 
LVEF (%) 
 
 
 
 
 
 
   Baseline 
 
 
 
 
 
 
     n 
xx 
 
xx 
 
xx 
 
     Mean 
xx.x 
 
xx.x 
 
xx x 
 
     SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
     Median 
xx.x 
 
xx.x 
 
xx.x 
 
     Minimum 
xx 
 
xx 
 
xx 
 
     Maximum 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
   Cycle X Day X 
 
 
 
 
 
 
     n 
xx 
xx 
x 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx  
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Median 
xx.x 
xx x 
xx.x 
xx.x 
xx.x 
xx.x 
     Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
     Maximum 
xx 
x 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
   Cycle N Day N 
 
 
 
 
 
 
 
 
 
 
 
 
 
   End of Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Last Observation on Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Maximum Post-baseline Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Minimum Post-baseline Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. Repeated or unscheduled tests are not summarized for each 
scheduled visit, but are included for summaries of last observation on treatment, maximum and minimum post-baseline values. The End of Treatment value is based on the CRF visit. 
Last observation on treatment is defined as the last non-missing value on or prior to end of treatment period + 7.  
Source Data: adam.adeg; Listing 16.2.8.3.5. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Page 121 of 190 
 
Table 15.4.1.1:  Summary of Patritumab Concentration (ug/mL) from Sparse PK Sampling  
Pharmacokinetic Analysis Set 
HRG High 
Sample Times 
Treatment  
C1D1 
Pre-Infusion 
C1D1 
End of Infusion 
C2D1 
Pre-Infusion 
 
 
C3D1 
Pre-Infusion 
C3D1 
End of Infusion 
End of Treatment 
 
 
 
 
 
 
 
 
 
Patritumab+ cetuximab + 
cisplatin  or carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
 
  Mean 
xx.xxx  
       xx.xxx 
      xx.xxx 
      xx.xxx 
xx.xxx 
xx.xxx 
 
  SD 
xx.xxx  
       xx.xxx 
      xx.xxx 
      xx.xxx 
xx.xxx 
xx.xxx 
 
  CV% 
xx.xxx  
       xx.xxx 
      xx.xxx 
      xx.xxx 
xx.xxx 
xx.xxx 
 
  SEM 
xx 
xx 
xx 
xx 
xx 
xx 
 
  Geom. Mean 
xx 
xx 
xx 
xx 
xx 
xx 
 
  Geom. CV% 
xx 
xx 
xx 
xx 
xx 
xx 
 
  Minimum 
xx.xxx  
       xx.xxx 
      xx.xxx 
      x.xxx 
xx.xxx 
xx.xxx 
 
  1st Quartile 
xx.xxx  
       xx.xxx 
      xx.xxx 
      xx.xxx 
xx.xxx 
xx.xxx 
 
  Median 
xx.xxx  
       xx.xxx 
      xx xxx 
      xx.xxx 
xx.xxx 
xx.xxx 
 
  3rd Quartile 
xx.xxx  
       xx.xxx 
      x xxx 
      xx.xxx 
xx.xxx 
xx.xxx 
 
  Maximum 
xx.xxx  
       xx.xxx 
      xx. xx 
      xx.xxx 
xx.xxx 
xx.xxx 
 
 
 
 
 
 
 
 
 
Notes: Concentrations below the lower limit of quantitation (BLQ) are et to zero fo  the calculation of descriptive statistics. If any concentration at a    
            time point is BLQ, the geometric mean at that time po t is not c lculated and is presented as “NC”. 
            CxDx = Cycle x Day x 
Source Data: adam.adpk; Listing 16.2.5.2.1. 
 
Programming Note: List scheduled times as shown in table 8 1 of the protocol. 
Programming Note: continue for HRG Low and Overall on the next page 
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Page 122 of 190 
 
Table 15.4.1.2:  Summary of Patritumab Concentration (ug/mL) from Intensive PK Sampling at Cycle 1 
Pharmacokinetic Analysis Set 
HRG High 
Sample Times 
Treatment  
C1D1 
Pre-Infusion 
C1D1 
End of 
Infusion 
C1D1 
3  Hours Post 
Infusion 
 
 
C1D1 
4  Hours Post 
Infusion 
C1D1 
5  Hours Post 
Infusion 
C1D1 
6 Hours Post 
Infusion 
C1D1 
7  Hours Post 
Infusion 
 
 
 
 
 
 
 
 
Patritumab+ cetuximab + 
cisplatin  or carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx. xx  
xx.xxx  
xx.xxx  
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  CV% 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  SEM 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. Mean 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. CV% 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Minimum 
xx.xxx  
xx.xxx  
xx.xxx  
x xxx  
xx.xxx  
xx.xxx  
xx.xxx  
   1st Quartile 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Median 
xx.xxx  
xx.xxx  
xx x x  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  3rd Quartile 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Maximum 
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
 
 
 
 
 
Notes: Concentrations below the lower limit of quantitation (BLQ) a
 set t  zero for the calculation of descriptive statistics. If any concentration at a    
            time point is BLQ, the geometric mean at that time point is not calculated and is presented as “NC”. 
            CxDx = Cycle x Day x 
Source Data: adam.adpk; Listing 16.2.5.2.1. 
 
Programming Note: List scheduled times as shown in table 8.2 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
 
 
 
 
 
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Page 123 of 190 
 
Table 15.4.1.2:  Summary of Patritumab Concentration (ug/mL) from Intensive PK Sampling at Cycle 1 
Pharmacokinetic Analysis Set 
HRG High 
 
Sample Times 
 
Treatment   
C1D2 
24  Hours Post 
Infusion 
C1D3 
48  Hours Post 
Infusion 
C1D8 
168  Hours Post 
Infusion 
C1D15 
336  Hours Post 
Infusion 
C1D21 
504  Hours Post 
Infusion 
 
 
 
 
 
 
 
 
Patritumab+ cetuximab + 
cisplatin  or carboplatin 
 
 
 
 
 
 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
 
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
 
  CV% 
xx.xxx  
xx.xxx  
xx.xxx  
xx xx   
xx.xxx  
 
  SEM 
xx 
xx 
xx 
xx 
xx 
 
  Geom. Mean 
xx 
xx 
xx 
xx 
xx 
 
  Geom. CV% 
xx 
xx 
xx 
xx 
xx 
 
   Minimum 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
 
   1st Quartile 
xx.xxx  
xx.xxx  
xx.x x  
xx.xxx  
xx.xxx  
 
  Median 
xx.xxx  
xx.xxx  
xx.xx   
xx.xxx  
xx.xxx  
 
  3rd Quartile 
xx.xxx  
xx.xxx  
x.xxx  
xx.xxx  
xx.xxx  
 
  Maximum 
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
xx.xxx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations below the lower limit of quantitation (BLQ) ar  set to ero 
r the calculation of descriptive statistics. If any concentration at a    
            time point is BLQ, the geometric mean at that time point is not alculated and is presented as “NC”. 
            CxDx = Cycle x Day x 
Source Data: adam.adpk; Listing 16.2.5.2.1. 
 
Programming Note: List scheduled times as shown in table 8 2 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page
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Page 124 of 190 
 
Table 15.4.1.3:  Summary of Cetuximab Concentration (ug/mL) from Intensive PK Sampling at Cycle 1  
Pharmacokinetic Analysis Set 
HRG High 
Sample Times 
Treatment  
C1D1 
Pre-Infusion 
C1D1 
End of Infusion 
 
 
C1D1 
4  Hours Post 
Infusion 
C1D1 
5  Hours Post 
Infusion 
C1D1 
6 Hours Post 
Infusion 
C1D1 
7  Hours Post 
Infusion 
 
 
 
 
 
 
 
Patritumab + cetuximab + 
cisplatin  or carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
  N 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
x .xxx  
xx.xxx  
xx.xxx  
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx. xx  
xx.xxx  
xx.xxx  
  CV% 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  SEM 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. Mean 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. CV% 
xx 
xx 
xx 
xx 
xx 
xx 
  Minimum 
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
xx.xxx  
xx.xxx  
   1st Quartile 
xx.xxx  
xx.xxx  
x.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Median 
xx.xxx  
xx.xxx  
x .xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  3rd Quartile 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Maximum 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
 
 
 
 
Placebo + cetuximab + 
cisplatin  or carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
  N 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  … 
 
 
 
 
 
 
 Continue above 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations below the lower limit of quantitation (BLQ) are set to zero for the calculation of descriptive statistics. If any concentration at a    
            time point is BLQ, the geometric mean at that time point is not calculated and is presented as “NC”. 
            CxDx = Cycle x Day x 
Source Data: adam.adpk; Listing 16.2.5.2.2. 
 
Programming Note: List scheduled times as shown in table 8.2 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page  
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Page 125 of 190 
Table 15.4.1.3:  Summary of Cetuximab Concentration (ug/mL) from Intensive PK Sampling at Cycle 1  
Pharmacokinetic Analysis Set 
HRG High 
 
Sample Times 
 
Treatment   
C1D2 
24  Hours Post 
Infusion 
C1D3 
48  Hours Post 
Infusion 
C1D8 
168  Hours Post 
Infusion 
 
 
 
 
 
 
 
 
 
 
Patritumab+ cetuximab + 
cisplatin  or carboplatin 
 
 
 
 
 
 
 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
 
 
 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
  CV% 
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
  SEM 
xx 
xx 
xx 
 
 
 
  Geom. Mean 
xx 
xx 
xx 
 
 
 
  Geom. CV% 
xx 
xx 
xx 
 
 
 
   Minimum 
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
   1st Quartile 
xx.xxx  
xx.xxx  
xx.x x  
 
 
 
  Median 
xx.xxx  
xx.xxx  
xx.xx   
 
 
 
  3rd Quartile 
xx.xxx  
xx.xxx  
x.xxx  
 
 
 
  Maximum 
xx.xxx  
xx.xxx  
xx xxx  
 
 
 
 
 
 
 
 
 
 
Placebo + cetuximab + 
cisplatin  or carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
  N 
xx 
xx 
xx 
 
 
 
  Mean 
xx.xxx  
xx.xx   
xx.xxx  
 
 
 
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
  … 
 
 
 
 
 
 
 Continue above 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations below the lower limit of quantitation (BLQ) are set to zero for the calculation of descriptive statistics. If any concentration at a    
            time point is BLQ, the geometric mean at that time point is not calculated and is presented as “NC”. 
            CxDx = Cycle x Day x 
Source Data: adam.adpk; Listing 16.2.5.2.2. 
 
Programming Note: List scheduled times as shown in table 8.2 of the protocol. 
Programming Note: continue for HRG Low and Overall on the next page 
  
 
 
 
 
 
 
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Page 126 of 190 
 
 
Table 15.4.1.4:  Summary of Cisplatin Concentration (ug/mL) from Intensive PK Sampling at Cycle 1  
Pharmacokinetic Analysis Set 
HRG HIgh 
Sample Times 
Treatment  
C1D1 
Pre-Infusion 
C1D1 
End of Infusion 
C1D1 
6 Hours Post 
Infusion 
C1D1 
7  Hours Post 
Infusion 
C1D2 
24  Hours Post 
Infusion 
C1D3 
48  Hours Post 
Infusion 
 
 
 
 
 
 
 
Patritumab + cetuximab + 
cisplatin   
 
 
 
 
 
 
 
 
 
 
 
 
 
  N 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
xx xx  
xx.xxx  
xx.xxx  
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  CV% 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  SEM 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. Mean 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. CV% 
xx 
xx 
xx 
xx 
xx 
xx 
  Minimum 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
   1st Quartile 
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Median 
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  3rd Quartile 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Maximum 
xx.xxx  
xx.xxx  
x xxx  
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
 
 
 
 
Placebo + cetuximab + 
cisplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
  N 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  … 
 
 
 
 
 
 
 Continue above 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations below the lower limit of quantitation (BLQ) are set to zero for the calculation of descriptive statistics. If any concentration at a    
            time point is BLQ, the geometric mean at that time point is not calculated and is presented as “NC”. 
            CxDx = Cycle x Day x 
Source Data: adam.adpk; Listing 16.2.5.2.3. 
 
Programming Note: List scheduled times as shown in table 8.2 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Page 127 of 190 
Table 15.4.1.5:  Summary of Carboplatin Concentration (ug/mL) from Intensive PK Sampling at Cycle 1  
Pharmacokinetic Analysis Set 
HRG High 
Sample Times 
 
Treatment  
C1D1 
Pre-Infusion 
C1D1 
End of Infusion 
C1D1 
5  Hours Post 
Infusion 
C1D1 
6 Hours Post 
Infusion 
C1D1 
7  Hours Post 
Infusion 
C1D2 
24  Hours Post 
Infusion 
C1D3 
48  Hours Post 
Infusion 
 
 
 
 
 
 
 
 
Patritumab + cetuximab + 
carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  N 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx. xx  
xx.xxx  
xx.xxx  
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  CV% 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  SEM 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. Mean 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Geom. CV% 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Minimum 
xx.xxx  
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
xx.xxx  
xx.xxx  
   1st Quartile 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Median 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  3rd Quartile 
xx.xxx  
xx.xxx  
xx xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  Maximum 
xx.xxx  
xx.xxx  
xx. xx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
 
 
 
 
 
 
 
 
Placebo + cetuximab + 
carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  N 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
  Mean 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  SD 
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
xx.xxx  
  … 
 
 
 
 
 
 
 
 Continue above 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: Concentrations below the lower limit of quantitation (BLQ) are set to zero for the calculation of descriptive statistics. If any concentration at a    
            time point is BLQ, the geometric mean at that time point is not calculated and is presented as “NC”. 
            CxDx = Cycle x Day x 
Source Data: adam.adpk; Listing 16.2.5.2.4. 
 
Programming Note: List scheduled times as shown in table 8.2 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
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Page 128 of 190 
Table 15.4.2.1: Summary of Patritumab PK Parameters at Cycle 1 
Pharmacokinetic Analysis Set 
 
                                                     HRG High       
Cycle 
Patritumab + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
AUClast 
Cmax 
(ug.day/mL) 
(ug/mL) 
Cycle 1 
 
 
 
 
 
Geometric mean 
 
 
Geometric CV% 
 
 
Arithmetic mean 
 
 
Arithmetic SD 
 
 
Median 
 
 
Min 
 
 
Max 
 
 
N 
 
 
 
 
 
 
 
 
            Note: If there are less than 3 values in the data series only the min, max, an  N a e presented. The other summary statistics are denoted as not calculated (NC). 
 If one or more of the values in a data series is zero, then do not calculate the geometric mean and geometric CV% and denote them as not applicable (NA). 
                      If an entire concentration-time profile is BLQ, PK parameters will b  reported as NC and set to missing for summary statistics. 
                      For the calculation for summary statistics of PK parame ers, al  NR a d NC values in a data series are set to missing. 
 
Source Data: adam.adpk; Listing 16.2.5.2.1. 
 
Programming Note: List scheduled times as shown in table 8.2 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 129 of 190 
Table 15.4.2.2: Summary of Cetuximab PK Parameters at Cycle 1 
Pharmacokinetic Analysis Set 
 
                   HRG High  
Cycle 
Patritumab + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
Placebo + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
AUClast 
Cmax 
AUClast 
Cmax 
(ug.day/mL) 
(ug/mL) 
(ug.day/mL) 
(ug/mL) 
Cycle 1 
 
 
 
 
 
 
 
 
 
Geometric mean 
 
 
 
 
Geometric CV% 
 
 
 
 
Arithmetic mean 
 
 
 
 
Arithmetic SD 
 
 
 
 
Median 
 
 
 
 
Min 
 
 
 
 
Max 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
            Note: If there are less than 3 values in the data series only the min  ma  and N are presented. The other summary statistics are denoted as not calculated (NC). 
 If one or more of the values in a data series is zero, then do not ca culate the geometric mean and geometric CV% and denote them as not applicable (NA). 
                      If an entire concentration-time profile is BLQ  PK param ters w ll be 
ported as NC and set to missing for summary statistics. 
                      For the calculation for summary statistics of K paramete
 all NR and NC values in a data series are set to missing. 
 
Source Data: adam.adpk; Listing 16.2.5.2.1. 
 
Programming Note: List scheduled times as shown in table 8 2 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page 
 
The following table follows Table 15.4.2.2: 
 
 
Table 15.4.2.3 
Summary of Cisplatin PK Parameters at Cycle 1  
Pharmacokinetic Analysis Set 
 
Table 15.4.2.4 
Summary of Carboplatin PK Parameters at Cycle 1  
Pharmacokinetic Analysis Set 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 130 of 190 
Table 15.4.2.5: Statistical Analysis of Cetuximab, Cisplatin, and Carboplatin PK Parameters at Cycle 1   
Pharmacokinetic Analysis Set 
 
HRG High 
 
Geometric LS Mean 
(95% CI) 
Ratio of Geometric LS means  
(90% CI) 
PK Parameter 
Patritumab + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
Placebo + cetuximab + 
cisplatin or carboplatin 
(N=xxx) 
 
Patritumab/Placebo 
 
 
 
 
Cetuximab 
 
 
 
    AUClast 
xx.x 
xx.x 
xx.x 
 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x] 
    Cmax 
xx.x 
xx.x 
xx.x 
 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x] 
Cisplatin 
 
 
 
    AUClast 
xx.x 
xx.x 
xx.x 
 
[xx.x, xx.x] 
[xx.x  xx x] 
[xx.x, xx.x] 
    Cmax 
xx.x 
xx.x 
xx.x 
 
[xx.x, xx.x] 
[x .x, xx.x] 
[xx.x, xx.x] 
Carboplatin 
 
 
 
    AUClast 
xx.x 
xx.x 
xx.x 
 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x] 
    Cmax 
xx.x 
xx.x 
xx.x 
 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x] 
 
 
 
 
Note: AUClast and Cmax will be log-transformed prior o nalysis. The geometric mean ratios and their two-sided 90% CIs for AUClast and Cmax between the 
patritumab arm and the placebo arm will be calculated using the e ponentiation of the differences and their CIs between treatments least square mean from the 
ANOVA. The ratios and their two-sided 90% CIs will be expressed relative to the placebo arm. 
 
Source Data: adam.adpk; Listing 16.2.5.2.2 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
 
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Page 131 of 190 
Table 15.5.1.1: Summary of Actual Results and Change from Baseline in FACT-H&N Total Score, FACT-H&N Subscale (HNS) Score, 
HNS Individual Symptom Score, and FACT-H&N Symptom Index (FHNSI) Score 
FACT-H&N Analysis Set 
HRG High 
PRO Measure 
   Visit 
Patritumab + cetuximab + cisplatin or carboplatin 
____(N=xxx)_____ 
Placebo + cetuximab + cisplatin or carboplatin 
____(N=xxx)_____ 
 
Result  
Change  
Result  
Change  
FACT-H&N Total Score 
 
 
 
 
   Baseline 
 
 
 
 
     n 
xx 
 
xx 
 
     Mean 
xx.x 
 
xx.x 
 
     SD 
xx.xx 
 
xx.xx 
 
Minimum 
xx 
 
xx 
 
Median 
xx.x 
 
xx.x 
 
Maximum 
xx 
 
xx 
 
 
 
 
 
 
   Cycle 2 Day 1 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Minimum 
xx 
xx 
xx 
xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
  Cycle 3 Day 1  
 
 
 
 
     n 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Minimum 
xx 
xx 
xx 
xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
     Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
... 
 
 
 
 
Continue with Cycle 4 Day 1, Cycle 5 Day 1 and additional cycles as required. Last visit will be End of Study Treatment. Then continue with FACT-H&N Subscale 
(HNS) Score, HNS Individual Symptom Score, and FACT-H&N Symptom Index (FHNSI) Score 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. 
PRO assessments obtained at the end of treatment visit or at scheduled timepoints with fewer than 5 subjects in any treatment arm are not included. 
 
Source Data: adam.adqs; Listing 16.2.9.1, 16.2.9.2 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 132 of 190 
 
 
Table 15.5.1.2: Statistical Analysis of the Change from Baseline in the FACT-H&N total score, the FACT-H&N HNS,  
HNS individual symptom score, and the FACT-H&N FHNSI score  
FACT-H&N Analysis Set 
 
HRG High 
PRO 
Measure 
Timepoint 
LS mean  
(95% CI) 
Difference between LS means   
 (95% CI) 
Patritumab + cetuximab +  
cisplatin or carboplatin  
(N=xxx) 
Placebo + cetuximab +  
cisplatin or carboplatin  
(N=xxx) 
Patritumab - placebo 
 
 
 
 
 
FACT-H&N 
total score 
Cycle 2 Day 1 
xx.x 
xx.x 
xx.x 
 
 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x] 
 
 
 
 
 
 
Cycle 3 Day 1 
xx.x 
xx.  
xx.x 
 
 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x] 
 
 
 
 
 
 
Cycle 5 Day 1 
xx.x 
xx.x 
xx.x 
 
 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x] 
 
 
 
 
 
 
Overall  
 
 
xx.x 
 
 
 
 
[xx.x, xx.x] 
 
 
 
 
 
Programming notes: display all timepoints with at least five bser ations per group. Continue with the FACT-H&N HNS,  
Each of HNS individual symptom score, and the FACT-H&N FHNSI score 
 
Notes: The mixed model includes treatment, timepoint, treatment x timepoint, and baseline as fixed effects and subject as random effect. If the interaction effect 
was not significant (p >0.10), the model was rerun without the interaction term and the overall LS mean differences and CIs were estimated.  
PRO assessments obtained at the end of treatment visit or at scheduled timepoints with fewer than 5 subjects in any treatment arm are not included. 
The final model [included] [did not include] an interaction term. The xxx covariance structure was used to estimate the interaction model. 
The xxx covariance structure was used to estimate the final model. 
 
Programming note: Specify in footnote whether final model included an interaction term. Overall LS mean differences are not displayed if the interaction term is significant.  
Source Data: adam.adqs; Listing 16.2.9.1, 16.2.9.2 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 133 of 190 
 
Table 15.5.1.3: Summary of Actual Results and Change from Baseline in EQ-5D Index 
EQ-5D Analysis Set 
 
HRG High 
PRO Measure 
   Visit 
Patritumab + cetuximab + cisplatin or carboplatin 
____(N=xxx)_____ 
Placebo + cetuximab + cisplatin or carboplatin 
____(N=xxx)_____ 
 
Result  
Change  
Result  
Change  
   Baseline 
 
 
 
 
     n 
xx 
 
xx 
 
     Mean 
xx.x 
 
xx.x 
 
     SD 
xx.xx 
 
xx.xx 
 
Minimum 
xx 
 
xx 
 
Median 
xx.x 
 
xx.x 
 
Maximum 
xx 
 
xx 
 
 
 
 
 
 
   Cycle 2 Day 1 
 
 
 
 
     n 
xx 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Minimum 
xx 
xx 
xx 
xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
  Cycle 3 Day 1  
 
 
 
 
     n 
x 
xx 
xx 
xx 
     Mean 
xx.x 
xx.x 
xx.x 
xx.x 
     SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
     Minimum 
xx 
xx 
xx 
xx 
     Median 
xx.x 
xx.x 
xx.x 
xx.x 
     Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
Notes: The baseline value is defined as the last non-missing value before initial administration of study treatment. 
PRO assessments obtained at the end of treatment visit or at scheduled timepoints with fewer than 5 subjects in any treatment arm are not included. 
 
Source Data: adam.adqs; Listing 16.2.9.1, 16.2.9.2 
Programming Note: continue for HRG Low and Overall on the next page  
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 134 of 190 
 
The following table follows Table 15.5.1.3: 
 
 
 
Table 15.5.1.4 
Summary of Actual Results and Change from Baseline in VAS Score 
EQ-5D Analysis Set 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 135 of 190 
Figure 15.1.1 
CONSORT Diagram 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 136 of 190 
Figure 15.2.1.1 
Kaplan-Meier Plot of Progression Free Survival (PFS) by Treatment Group  
Full Analysis Set 
 
                 HRG High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source Data: adam.adtte; Listing 16.2.6.1 
Programming Note: continue for HRG Low and Overall on the next page  
  
 
Progression Free Survival Probability (%)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Study Month
0
2
4
6
8
10
12
14
Number of Patients at Risk
Patritumab
Placebo
         217           46           15            8            4            2            1            1
         110           17            8            3            0            0            0            0
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 137 of 190 
 
Programming note:  Add the legend for different treatment arms in the plot. 
                                 Show the timepoint in the survival line when there is censored subject. 
 
Replace the second sentence with “Medications taken on or after the first dose of study medication will be classified as concomitant medications”. 
 
 
The following figure follows Figure 15.2.1.1 and change the label for the y-axis accordingly. 
 
 
Figure 15.2.1.3 
Kaplan-Meier Plot of Progression Free Survival (PFS) for Different HRG Cutoffs by Treatment Group 
 Full Analysis Set 
 
Programming Note: Change the subtitle to “HRG Cutoff: XX; HRG High of Cutoff” and continue for HRG Cutoff: XX; HRG Low of Cutoff XX and HRG Cutoff: XX; Overall of Cutoff XX. 
Continue for Different HRG cuteoffs. 
 
Figure 15.2.2.1 
Kaplan-Meier Plot of Overall Survival (OS) by Treatment Group 
 Full Analysis Se  
 
Figure 15.2.2.3 
Kaplan-Meier Plot of Overall Surv val (O ) for Different HRG Cutoffs by Treatment Group  
F l  Ana ysis Set 
 
Programming Note: Change the subtitle to “HRG Cutoff: XX; HRG High of C toff” a d continue for HRG Cutoff: XX; HRG Low of Cutoff XX and HRG Cutoff: XX; Overall of Cutoff XX. 
Continue for Different HRG cuteoffs. 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                                              Page x of y                                                
Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 138 of 190 
Figure 15.2.1.2 
Forest Plot of Progression Free Survival (PFS) for Selected Subgroups  
Full Analysis Set 
 
 
Figure 15.2.3: 
Waterfall Plot of Best (Minimum) Percent Change in Sum of Longest Diameters from Baseline in Target Lesions 
Full Analysis Set 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 139 of 190 
HRG High 
  
 
      
Patritumab + cetuximab + cisplatin or carboplatin 
Placebo + cetuximab +cisplatin or carboplatin  
Minimum Change (%) 
Minimum Change (%) 
 
 
n 
Mean 
SD 
Median 
Minimum 
M ximum 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx.xx 
 
Note: For each subject, the minimum percent change from baseline in the sum of Longest Diameters for all target lesions is represented by a vertical 
line. 
 
Source Data: adam.adrs; Listing  xxxx 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
Minimum Percent Change
-7 0
-6 0
-5 0
-4 0
-3 0
-2 0
-
0
0
0
2 0
3 0
4 0
5 0
Minimum Percent Change
-7 0
-6 0
-5 0
-4 0
-3 0
-2 0
-
0
0
0
2 0
3 0
4 0
5 0
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 140 of 190 
Figure 15.2.4: 
Swimmer Plot of Tumor Response and Treatment Duration 
Full Analysis Set 
 
HRG High 
Treatment: Patritumab + cetuximab + cisplatin or carboplatin 
  
 
      
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 141 of 190 
Source Data: adam.adrs; Listing  xxxx 
Programming Note: continue for Placebo + cetuximab +cisplatin or carboplatin . Continue for HRG Low. 
1. 
Please sort RS by date first then do the best response 
2. 
Sort the plot by largest AVAL1. Each subject is a bar. 
3. 
Add symbol of CR/PR start date of CR/PR subject (AVAL2). 
4. 
Add symbol for status at the end of each bar (STATUS) 
 
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Page 142 of 190 
Figure 15.4.1.1 Mean Plasma Concentration of Patritumab by Time from Sparse PK Sampling 
Pharmacokinetic Analysis Set 
 
-----Lower limit of quantification (<0.1) 
Note: Mean Plasma Concentration data are plotted by C1D1 Pre-Infusion, C1D1 End of Infusion, C2D1 
Pre-Infusion, C3D1 Pre-Infusion, C3D1 End of Infusion and End of Tr
tment.  
CxDx = Cycle x Day x 
If mean is BLQ, then these are plotted as zero on the linear scale and missing on the semi-log 
Scale. 
Source Data: adam.adpk; Listing 16.2.5.2.1 
 
 
 
 
LLOQ = 0. 1 ( ug/ mL)
Ser um Pat r i t umab concent r at i on ( ug/ mL)
0
100
200
300
400
Ti me Poi nt
 
 
a  
 
 
 
C1D1 Pr eI
C1D1 EOI
C2D1 Pr eI
C3D1 Pr eI
C3D1 EOI
EOT
C1D1 Pr eI
C1D1 EOI
C2D1 Pr eI
C3D1 Pr eI
C3D1 EOI
EOT
C1D1 Pr eI
C1D1 EOI
C2D1 Pr eI
C3D1 Pr eI
C3D1 EOI
EOT
C1D1 Pr eI
C1D1 EOI
C2D1 Pr eI
C3D1 Pr eI
C3D1 EOI
EOT
C1D1 Pr eI
C1D1 EOI
C2D1 Pr eI
C3D1 Pr eI
C3D1 EOI
EOT
C1D1 Pr eI
C1D1 EOI
C2D1 Pr eI
C3D1 Pr eI
C3D1 EOI
EOT
Tr eat ment  Gr oup
Pat r i t umab
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Page 144 of 190 
The following figures follows Figure 15.4.1.2 
 
Figure 15.4.1.3 Mean Plasma Concentration of Cetuximab by Time from Intensive PK Sampling  
Pharmacokinetic Analysis Set 
 
Similar as Table 15.4.1.3, will plot data by hours of 0, 3, 4, 5, 6, 7, 24, 48, and 168.  
 
Figure 15.4.1.4 Mean Plasma Concentration of Cisplatin by Time from Intensive PK Sampling  
Pharmacokinetic Analysis Set 
 
Similar as Table 15.4.1.4, will plot data by hours of 0, 5, 6, 7, 24, and 48. 
 
Figure 15.4.1.5 Mean Plasma Concentration of Carboplatin by Time from Intensive PK Sampling  
Pharmacokinetic Analysis Set 
 
Similar as Table 15.4.1.5, will plot data by hours of 0, 4.5, 5, 6, 7, 24, and 48. 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 145 of 190 
 
Figure 15.4.2.1 
Boxplot of Patritumab PK Parameters at Cycle 1  
Pharmacokinetic Analysis Set 
 
                                                               HRG High 
 
 
 
 
 
Source Data: adam.adpk; Listing 16.2.5.2.1 
 
Programming Note: X-axis only presents one treatment group as Patritumab + cetuximab + cisplatin or carboplatin 
                                Y-axis presents AUClast (ug.day/mL) 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 146 of 190 
 
 
 
 
The following figures follows Figure 15.4.2.1 
 
 
 
Figure 15.4.2.2 
Boxplot of Cetuximab PK Parameters at Cycle 1 by Treatment  
Pharmacokinetic Analysis Set 
 
Figure 15.4.2.3 
Boxplot of Cisplatin PK Parameters at Cyc e 1 by Treatment  
Pharmacokinetic Analysis Set 
 
Figure 15.4.2.4 
Boxplot of Carboplatin PK Parameters at Cycle 1 by Treatment  
Pharmacokinetic Analys s Set
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 147 of 190 
Figure 15.5.1.1 Plot of Cumulative Distribution Function of Change from Baseline on FACT-H&N HNS Score  
FACT-H&N Analysis Set 
 
                                      HRG High 
 
 
Source Data: adam.adqs; Listing 16.2.9.1, 16.2.9.2 
Programming Note:  x-axis will be displayed as follows:  Cycle 2 Day 1 Change from Baseline; Cycle 3 Day 1 Change from Baseline; Cycle 5 Day 1 Change from  
Programming Note: continue for HRG Low and Overall on the next page 
Baseline and End-of-Treatment Change from Baseline. X-axis values will range from minimum change to maximum change depending on the data.   
Display the legend  for the two treatment groups: ○ Patritumab + cetuximab + cisplatin or carboplatin 
                                                                                □ Placebo + cetuximab + cisplatin or carboplatin 
 
Figure 15.6.1 Heregulin (HRG) Distribution  
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 148 of 190 
Full Analysis Set 
 
                                       
HRG High 
Treatment: Patritumab + cetuximab + cisplatin or carboplatin 
 
 
 
 
Source Data: adam.adxx 
Programming Note: X-axis presents heregulin 
                                Y-axis presents frequency (number of people with the heregulin range) 
Programming Note: continue for Placebo + cetuximab + cisplatin or carboplatin and continue for HRG Low and Overall on the next page 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 149 of 190 
 
 
Listing 16.2.1.1: Subject Disposition 
All Screen Subjects 
 
 
 
Subject ID/ 
Group/Age/ 
Gender 
 
 
Screen Fail/ 
Reason 
First Dose Date of 
Patritumab/ 
Cetuximab/ 
Cisplatin/Capboplatin 
Last Dose Date (Day) of 
Patritumab/ 
Cetuximab/ 
Cisplatin/Capboplatin 
Primary Reason for 
Discontinuation 
from Study 
Treatment 
Primary Reason for 
Discontinuation 
from Extension 
Treatment 
 
Follow-up 
Contact 
Date 
 
Started New 
Cancer 
Treatment 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin /xx/M 
No 
yyyy-mm-dd/ 
yyyy-mm-dd/ 
yyyy-mm-dd 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx) 
Completed 
xxx
xxxxxxx 
yyyy-mm-dd (xx) No 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin /xx/M 
No 
yyyy-mm-dd/ 
yyyy-mm-dd/ 
yyyy-mm-dd 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx) 
xxxxxxxxxxxx 
Did not continue in Ext 
yyyy-mm-dd (xx) Yes – yyyy-mm-dd 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin /xx/M 
Yes – xxxxxxxx x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adsl 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 150 of 190 
Listing 16.2.1.2: Deaths 
Full Analysis Set 
 
HRG High 
 
Subject ID/ 
Group/Age/ 
Gender 
First Dose Date of 
Patritumab/ 
Cetuximab/ 
Cisplatin/Capboplatin 
Last Dose Date (Day) of 
Patritumab/ 
Cetuximab/ 
Cisplatin/Capboplatin 
 
 
Death Date 
(Day) 
 
 
 
Primary Cause of Death 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/M 
yyyy-mm-dd/ 
yyyy-mm-dd/ 
yyyy-mm-dd 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx) 
yyyy-mm-dd (xx) 
xxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/M 
yyyy-mm-dd/ 
yyyy-mm-dd/ 
yyyy-mm-dd 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx)/ 
yyyy-mm-dd (xx) 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Source: adam.adsl 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Listing 16.2.2.1: Inclusion/Exclusion Criteria 
All Screen Subjects 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
 
Inclusion/Exclusion 
Assessment Date 
 
 
Failed 
Inclusion/Exclusion 
Criteria 
 
 
If Yes, Specify Criteria [a] 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin /xx/M 
yyyy-mm-dd 
No 
  
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin /xx/M 
yyyy-mm-dd 
Yes 
1, 2, x 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin /xx/M 
yyyy-mm-dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Notes: [a] See appended pages of this listing for a complete list of the inclusion and exclusion criteria from Protocol Version 2.0. 
 
Source: adam.adie, Protocol U31287-A-U203 Version 2.0 (27Aug2015) 
 
Programming note: Append next 2 pages to end of this listing. 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 152 of 190 
Listing 16.2.2.1: Inclusion Criteria 
 
________________________________________________________________________________________________________________________________________________ 
 
Subjects must satisfy all of the following criteria to be included in the study: 
 
1 
 
2 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________________________________________________________________________________ 
Source: adam.adie, Protocol U31287-A-U203 Version 2.0 (27Aug2015) 
 
 
 
Programming note: list all inclusion criteria from the protocol. 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 153 of 190 
Listing 16.2.2.1: Exclusion Criteria 
 
________________________________________________________________________________________________________________________________________________ 
 
Subjects who meet any of the following criteria will not be included in the study: 
 
1 
 
2 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________________________________________________________________________________ 
Source: adam.adie, Protocol U31287-A-U203 Version 2.0 (27Aug2015) 
 
 
Programming note: list all exclusion criteria from the protocol. 
 
 
 
 
 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 154 of 190 
Listing 16.2.2.2: Informed Consent 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
 
Study Informed 
Consent Date (Day) 
Consented to 
Pharmacogenomic 
Sampling 
Sample Taken for 
Pharmacogenomic/ 
Date (Day) 
 
Consented to 
Tumor Tissue Sampling 
Sample Taken for 
Tumor Tissue/ 
Date (Day) 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin /xx/M 
yyyy-mm-dd (xx) 
Yes 
Yes – yyyy-mm-dd (xx) 
Yes 
Yes – yyyy-mm-dd (xx) 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin /xx/M 
yyyy-mm-dd (xx) 
No 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin /xx/M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adsl, adam.adpg 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 155 of 190 
Listing 16.2.2.3: Protocol Deviation 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
 
 
Date of Deviation (Day) 
 
 
Deviation Class 
 
 
Deviation Text 
 
 
Source [a] 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin /xx/M 
yyyy-mm-dd (xx) 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
CRF 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin /xx/M 
yyyy-mm-dd (xx) 
xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxx xxxxxxx 
ICOTRIAL 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin /xx/M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: [a] ICOTRIAL deviations are obtained from the clinical monitoring database. CRF deviations are derived using CRF data. 
 
Source: adam.addv, ICOTRIAL 
 
Need to confirm if programmed deviations from CRF data is needed. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 156 of 190 
Listing 16.2.3: Subject Inclusion in Analysis Sets 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
 
 
Safety Analysis Set 
 
 
DLT Evaluable Set 
 
 
Pharmacokinetic Analysis Set 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/M 
Yes 
No – Did not receive 80% of cetuximab 
Yes 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/M 
No – Not Dosed 
No – Not Dosed 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adsl 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 157 of 190 
Listing 16.2.4.1: Demographic Data 
Full Analysis Set 
 HRG High 
Subject ID/Group 
Date of 
Birth 
Study Informed 
Consent Date (Day) 
Age  
(yrs) [a] 
Gender 
Ethnicity 
Race 
Height 
(cm) 
Baseline 
Weight 
(kg) 
 
 
 
 
 
 
 
 
 
xxxxxx/Patritumab+ 
cetuximab + cisplatin or 
carboplatin 
yyyy-mm-dd 
yyyy-mm-dd (xx) 
xx 
M 
Hispanic/Latino 
xxxxxxxxxx 
xxx.x 
xxx.x 
 
 
 
 
 
 
 
 
 
xxxxxx/Patritumab+ 
cetuximab + cisplatin or 
carboplatin 
yyyy-mm-dd 
yyyy-mm-dd (xx) 
xx 
F 
Non Hispanic/Non Latino 
xxxxxxxxx 
xxx.x 
xxx.x 
 
 
 
 
 
 
 
 
 
xxxxxx/Patritumab+ 
cetuximab + cisplatin or 
carboplatin 
yyyy-mm-dd 
yyyy-mm-dd (xx) 
xx 
M 
Hispanic/Latino 
Other: xxxxxxxxx 
xxx.x 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] Age is calculated as the number of complete years between date of birth and date of informed consent. 
 
 
Source: adam.adsl 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 158 of 190 
Listing 16.2.4.2: Pregnancy Test Results 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Visit 
Pregnancy 
Test Done? 
Date of Test 
(Day) 
Method 
Result 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/F 
Screening 
Yes 
yyyy-mm-dd (xx) 
Urine 
Negative 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/F 
Screening 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adlb 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 159 of 190 
Listing 16.2.4.3: Medical/Surgical History 
Full Analysis Set 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Event/Diagnosis 
 
Onset Date 
(Day) 
Continuing 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/F 
xxxxxxxxxxxxxxxxxxxx 
 
yyyy-mm-dd (xxx) 
Yes 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin 
/xx/F 
xxxxxxxxxxxxxxxxxxxx 
 
yyyy-mm-dd (xxx) 
No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.admh 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 160 of 190 
Listing 16.2.4.4.1: Cancer History for SCCHN 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
 
 
Cancer 
Type 
Histology 
Date of Initial  
Histologic 
Diagnosis 
Time from  
Initial Diagnosis to 
Study Treatment 
(Months) [a] 
Tumor Staging 
at Study 
Entry 
Grade 
Date of 
Biopsy 
Anatomical  
Location 
Type of Biopsy 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin / 
xx/F 
xxxxx 
xxxxxxx 
yyyy-mm-dd 
xxx 
IA 
Well Differentiated 
yyyy-mm-dd 
xxxxxxxxxx 
FNAB 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin/ 
xx/M 
xxxxxxxx xxxxxxxx 
yyyy-mm-dd 
xxx 
IIB 
Mod rat ly 
Differentiated 
yyyy-mm-dd 
xxxxxxxxxx 
Core Needle 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxxx 
yyyy-mm-dd 
xxx 
Oth r: xxx 
Undifferentiated 
yyyy-mm-dd 
xxxxxxxxxx 
Surgery: xxx 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxxxxxxx yyyy-mm-dd 
xxx 
V 
Moderately 
Differentiated 
yyyy-mm-dd 
xxxxxxxxxx 
Excisional 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] Time from initial diagnosis to study treatment = (date of initial administration of any study treatment – date of diagnosis + 1)/365.25x12. 
 
Source: adam.admh 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 161 of 190 
Listing 16.2.4.4.2: Prior Head and Neck Systemic Cancer Therapy  
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Intended for 
Best Response [a] 
Agent Name 
Start Date  
Stop Date 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin / 
xx/F 
xxxxxxxx 
PR 
xxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin / 
xx/M 
xxxxxxxx 
CR 
xxxxxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
 
 
 
 
 
 
 
 
SD 
xxxxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
 
 
 
 
 
 
 
 
PD 
xxxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: [a] CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease; NA=Not Applicable 
 
Source: adam.adcm 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 162 of 190 
Listing 16.2.4.4.3: Prior Radiation Therapy 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Any Prior Radiation 
Therapy 
 
Indication 
Start Date 
End Date 
Location 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
Yes 
xxxxxxxxxxxxxxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
xxxxxxxxxxx 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/M 
Yes 
xxxxxxxxxxxxxxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
xxxxxxxxxxx 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/M 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adcm 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 163 of 190 
Listing 16.2.4.5: Prior/Concomitant Medication 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
C: Class  
W: WHO Drug Term  
V: Verbatim Name  
S: Start Date (Day) 
E: Stop Date (Day) 
O: Ongoing  
Dose (Units) 
Frequency  
 
 
Indication 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
C: xxxxxxxxxxxxx 
W: xxxxxxxxxxxxx 
V: xxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E:  
O: Yes 
xxxxxxx (Other/xxxx) 
xxxxxxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/M 
C: xxxxxxxxxxxxx 
W: xxxxxxxxxxxxx 
V: xxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E: yyyy-mm-dd (xxx) 
O: No 
xxxxxxx (xxxx) 
xxxxxxxxxx 
xxxxxxxxxxx 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
C: xxxxxxxxxxxxx 
W: xxxxxxxxxxxxx 
V: xxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E: yyyy-mm-dd (xxx) 
O: No 
xxxx xx (xxxx) 
xxxxxxxx 
xxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                  
Source: adam.adcm 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 164 of 190 
Listing 16.2.4.6: Non-Drug Treatment/Procedures 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Treatment/Procedure 
S: Start Date (Day) 
E: End Date ( Day) 
O: Ongoing 
Duration 
Indication 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
xxxxxxxxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E: yyyy-mm-dd (xxx) 
O: No:  
xxx 
xxxxxxxxxxx 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/M 
xxxxxxxxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E: 
O: Yes 
xxx 
xxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adcm 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 165 of 190 
Listing 16.2.5.1.1: Investigational Drug Patritumab Administration 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Visit 
Date of Infusion 
 (Day) 
Start Time/ 
Stop Time 
Dose Level 
(mg/kg) 
Actual Total Dose 
Administered 
(mg/kg) 
Was IV 
Completed? 
Reason for Change or 
Interruption 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/xx/F 
Cycle 1 Day 1 yyyy-mm-dd (xx) 
hh:mm/hh:mm 
 
xx 
xx 
No 
xxx 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/xx/M 
Cycle 1 Day 1 yyyy-mm-dd (xx) 
hh:mm/ hh:mm 
xx 
xx 
Yes 
xxx 
 
Cycle x Day 1 
yyyy-mm-dd (xx) 
hh:mm/ hh:mm 
xx 
xx 
Yes 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adex 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 166 of 190 
Listing 16.2.5.1.2: Cetuximab, Cisplatin, and Carboplatin Administration 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Visit 
Study Drug 
Date of Infusion 
 (Day) 
Start Time/ 
Stop Time 
Dose Level 
(unit) 
Actual Total Dose 
Administered 
(unit) 
Was IV 
Completed? 
Reason for Change or 
Interruption 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/xx/F 
Cycle 1 Day 1 
Cetuximab 
yyyy-mm-dd (xx) 
hh:mm/ hh:mm 
xx (mg/m2) 
xx (mg/m2) 
No 
xxx 
 
 
Cisplatin 
yyyy-mm-dd (xx) 
hh:mm/ hh:mm 
xx (mg/m2) 
xx (mg/m2) 
Yes 
xxx 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/xx/M 
Cycle 1 Day 1 
Cetuximab 
yyyy-mm-dd (xx) 
hh:mm/ hh:mm 
xx (mg m2  
xx (mg/m2) 
Yes 
xxx 
 
  
Carboplatin 
yyyy-mm-dd (xx) 
hh:mm/ hh:mm 
xx (mg) 
xx (mg) 
Yes 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adex 
Programming Note: continue for HRG Low and Overall on the next page. 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 167 of 190 
Listing 16.2.5.1.3: Patritumab, Cetuximab, and Cisplatin/Carboplatin Exposure 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
 
Study Drug 
Treatment Duration 
(Weeks) [a] 
Treatment Duration 
(Cycles) [a] 
Number of IV 
Received 
 
Cumulative Dose (unit) [b] 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/xx/F 
Patritumab 
xx.x 
xx.x 
xx 
xxx (mg/kg) 
 
Cetuximab 
xx.x 
xx.x 
xx 
xxx (mg/m2) 
 
Cisplatin/Carboplatin 
xx.x 
xx.x 
xx 
xxx (mg/m2) / xxx (mg) 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/xx/M 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] Treatment duration (in weeks) for Patritumab and Cisplatin/Carboplatin is calculated as (date of the last dose – date of the first dose + 21)/7.  
                 Treatment duration (in cycles) for Patritumab and Cisplatin/Carboplatin is calculated as (date of the last dose – date of the first dose + 21)/21.  
                 Treatment duration (in weeks) for Cetuximab is calculated as (date of the last dose – date of the first dose + 7)/7.  
                 Treatment duration (in cycles) for Cetuximab is calculated as (date of the last dose – date of the first dose + 7)/21.  
 
    [b] Total cumulative dose is the sum of doses taken by a subject across cycles. 
Source: adam.adex 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 168 of 190 
Listing 16.2.5.2.1: Patritumab Pharmacokinetic Sample Collection Time and Results  
Pharmacokinetic Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Visit 
Patritumab Infusion 
Date Start Time/ 
Stop Time (Day) 
Nominal 
Time Point [a] 
PK 
Sample 
Taken 
Date/Time of Sample 
Collection (Day) 
Sample  
Identification 
Number 
Result 
(unit) 
Excluded from 
Analysis:  
Reason if Y 
 
AUC_0-21d/ 
C_max 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/xx/F 
C1D1 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
Pre-Infusion 
Yes 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
xxx.x/xxxx.x 
 
 
 
1 h 
Yes 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
 
 
3 h 
Yes 
yyyy-mm-dd hh:mm (xx) 
xx xx 
xxxxxx  
Y:xxxxxxx 
 
 
 
 
4 h 
No 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
 
 
5 h 
 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
C1D2 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
24 h 
 
yyyy-mm-dd h :mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy mm-dd hh mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yy y-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/xx/F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] All nominal time points are relative to the end of infusion except for pre-infusion. 
 
Source: adam.adpk 
 
Programming Note: List scheduled times as shown in table 8.1 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 169 of 190 
Listing 16.2.5.2.2: Cetuximab Pharmacokinetic Sample Collection Time and Results  
Pharmacokinetic Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Visit 
Cetuximab Infusion 
Date Start Time/ 
Stop Time (Day) 
Nominal 
Time Point [a] 
PK 
Sample 
Taken 
Date/Time of Sample 
Collection (Day) 
Sample  
Identification 
Number 
Result 
(unit) 
Excluded from 
Analysis:  
Reason if Y 
 
AUC_0-21d/ 
C_max 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/xx/F 
C1D1 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
Pre-Infusion 
Yes 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
xxx.x/xxxx.x 
 
 
 
3 h 
Yes 
yyyy-mm-dd hh:mm (xx) 
xxxx 
xxxxxx  
Y:xxxxxxx 
 
 
 
 
4 h 
Yes 
yyyy-mm-dd hh:mm (xx) 
xx xx 
xxxxxx  
N 
 
 
 
 
5 h 
No 
yyyy-mm-dd hh:mm ( x) 
xxxxx 
xxxxxx  
N 
 
 
C1D2 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
24 h 
 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy-mm dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy-mm dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
xx 
yyyy-mm-dd 
hh:mm/hh:mm (xx) 
xx 
 
yyyy-mm-dd hh:mm (xx) 
xxxxx 
xxxxxx  
N 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Placebo+ 
cetuximab + 
cisplatin or 
carboplatin/xx/F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] All nominal time points are relative to the end of infusion except for pre-infusion. 
 
Source: adam.adpk 
 
Programming Note: List scheduled times as shown in table 8.1 of the protocol.  
Programming Note: continue for HRG Low and Overall on the next page. 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 170 of 190 
The following listings follow Table 16.2.5.2.2: 
 
 
Listing 16.2.5.2.3: Patritumab Pharmacokinetic Sample Collection Time and Results  
 
Listing 16.2.5.2.4: Cetuximab Pharmacokinetic Sample Collection Time and Results 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 171 of 190 
Listing 16.2.6.1.1: Target Tumor Assessment 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Lesion 
Number 
Location 
Visit 
Assessment Date 
(Day) 
Assessment 
Method  
Longest Diameter 
(mm) [a] 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin/ 
xx/F 
1 
xxxxxxxxxx 
Screening 
yyyy-mm-dd (xxx) 
Spiral CT Scan 
xxx 
 
  
  
Cycle x 
yyyy-mm-dd (xxx) 
Spiral CT Scan 
xxx 
 
 
 
 
 
 
 
 
2 
Other (xxxxxxxx) 
Screening 
yyyy-mm dd (xx ) 
Spiral CT Scan 
xxx 
 
 
 
Cycle x 
yyyy-mm-dd (xxx) 
Spiral CT Scan 
xxx 
 
 
 
 
 
 
 
 
SUM LD 
 
Screening 
yyyy-mm-dd (xxx) 
 
xxx 
 
 
 
Cycle x 
yyyy mm-dd (xxx) 
 
xxx 
 
  
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin/ 
xx/M 
x 
xxxxxxxxxx 
Screening 
yyy-mm-dd (xxx) 
xxxxxxxxxxxxx 
xxx 
 
x 
xxxxxxxxxx 
Cy le x 
yyyy-mm-dd (xxx) 
xxxxxxxxxxxxx 
xxx 
 
x 
xxxxxxxxxx 
Cycle x 
yyyy-mm-dd (xxx) 
xxxxxxxxxxxxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] Shortest for lymph nodes. SUM LD = Sum of longest diameters. 
 
Source: adam.adtm 
Programming note: sort by subject ID, lesion number, and visit. 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 172 of 190 
Listing 16.2.6.1.2: Non-Target Tumor Assessment 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Lesion 
Number 
Location 
Visit 
Assessment Date 
(Day) 
Assessment 
Method  
Status 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/xx/F 
1 
xxxxxxxxxx 
Screening 
yyyy-mm-dd (xxx) 
Spiral CT Scan 
 
Present 
 
 
 
Cycle x 
yyyy-mm-dd (xxx  
Spiral CT Scan 
Absent 
 
 
 
 
 
 
 
 
2 
Other (xxxxxxxx) 
Screening 
yyyy-mm-dd (xxx) 
Spiral CT Scan 
xxx 
 
 
 
Cycle x 
yyyy-mm-dd (xxx) 
Spiral CT Scan 
xxx 
 
  
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or 
carboplatin/xx/M 
x 
xxxxxxxxxx 
Screening 
yyyy-mm-dd (xxx) 
xxxxxxxxxxxxx 
 
xxx 
 
x 
xxxxxxxxxx 
Cycle x 
yyyy-mm-dd (xxx) 
xxxxxxxxxxxxx 
xxx 
 
x 
xxxxxxxxxx 
Cycle x 
yyy-mm-dd (xxx) 
xxxxxxxxxxxxx 
New 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adtm 
      
Programming note: sort by subject ID, lesion number, and visit. 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 173 of 190 
Listing 16.2.6.1.3: Overall Tumor Assessment 
Full Analysis Set 
 
     HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Visit 
Tumor  Response 
Assessment 
Performed? 
Date of Overall 
Response 
(Day) 
Target Lesion 
Overall Evaluation 
Non-Target 
Lesion Overall 
Evaluation 
Overall 
Evaluation 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
Cycle x 
Yes 
yyyy-mm-dd (xxx) 
Partial Response 
Non-CR/Non-PD 
Partial Response 
 
Cycle x 
Yes 
yyyy-mm-dd (xxx) 
Partial Response 
Complete Response 
Partial Response 
 
Cycle x 
No 
  
 
 
 
 
 
 
 
 
 
 
 
Cycle x 
Yes 
yyyy-mm-dd (xxx) 
Stable Disease 
Non-CR/Non-PD 
Stable Disease  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Source: adam.adrs 
   Programming Note: continue for HRG Low and Overall on the next page 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 174 of 190 
Listing 16.2.6.2: Progression-Free Survival and Overall Survival 
Full Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Randomization 
Date (Day) 
Date of 
Last Tumor 
Assessment 
(Day) 
Date of 
Last Contact  
When Alive 
(Day) 
Radiographic 
Progression?/ 
Date of  
Progression  
(Day) 
Death?/ 
Date of Death 
(Day) 
Progression 
Free Survival 
(Days) [a] 
Overall 
Survival 
(Days) [b] 
Time to Disease 
Progression 
(Days) [c] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin/ 
xx/F 
YYYY-MM-DD 
(xx) 
YYYY-MM-DD 
(xxx) 
YYYY-MM-DD 
(xxx) 
No 
Yes/YYYY-MM-DD 
(xxx) 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin/ 
xx/M 
 
 
YYYY-MM-DD 
(xxx) 
No 
No 
1 (C) 
xxx (C) 
1 (C) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (C) = censored observation 
            [a] PFS is defined as the time from the date of randomization 
 the earlier f the dates of the first objective documentation of radiographic disease progression (per RECIST  
v1.1 as assessed by investigator) or death due to any cause. Se  the SAP for censoring rules. 
            [b] OS is defined as the time from the randomization date to the d te of death. If there is no death reported for a subject before the cut-off date for OS analysis, OS is censored 
at the last contact date at which the subject is known to be alive   
            [c] Time to disease progression is defined as the time from the randomization date to the date of first objective documentation of radiographic disease progression (per RECIST 
v1.1 as assessed by investigator). See the SAP for censoring rules 
Source: adam.adtte 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 175 of 190 
Listing 16.2.6.3: Subjects with Complete Response (CR), Partial Response (PR), or Stable Disease (SD) 
Full Analysis Set 
 
HRG High 
Subject ID/Group/Age/Gender 
Best 
Overall 
Response 
Date of Earliest 
Response  
(Day) 
Radiographic 
Progression?/ 
Date of 
Progression 
(Day) 
Date of 
Last Tumor 
Assessment 
(Day) 
Duration of  
Response  
(Weeks) [a] 
Time to 
Response 
(Weeks) [b] 
Duration of 
SD 
(Weeks) [c] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + cisplatin or 
carboplatin/ 
xx/F 
 PR 
YYYY-MM-DD 
(xxx) 
Yes/YYYY-MM-
DD (xxx) 
YYYY-MM-DD 
(xxx) 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + cisplatin or 
carboplatin/ 
xx/F 
CR 
YYYY-MM-DD 
(xxx) 
No 
YYYY-MM-DD 
(xxx) 
xxx (C) 
xxx  
xxx (C) 
 
 
 
 
 
 
 
 
xxxxxx/ 
Placebo + cetuximab + cisplatin or 
carboplatin/ 
xx/M 
SD 
DDMMMYYYY 
(xxx) 
Yes/ 
DMMMYYYY 
(xxx) 
DDMMMYYYY 
(xxx) 
 
 
xxx 
 
 
 
 
 
 
 
 
 
Notes: (C) = censored observation 
       [a] Duration of response is defined as the time from the date f the fir t documentation of objective response (CR or PR) to the date of the first documentation of progressive 
disease (disease progression as assessed based upon tumor measurements and recorded on the CRF page “overall tumor assessment”). See the SAP for censoring rules.     
       [b] Time to response is defined as the time from the randomization date to the date of the first documentation of objective response (CR or PR). 
       [c] Duration of SD is defined for subjects whose best response is SD as the time from the date of randomization to the date of the first documentation of progressive disease 
(disease progression as assessed based upon tumor measurements and recorded on the CRF page “overall tumor assessment”). See the SAP for censoring rules.  
Source: adam.adtte 
  
 
 
Programming notes:   
 Sort by best overall response. 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 176 of 190 
Listing 16.2.7.1: Adverse Events 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
TEAE? 
S: Class  
P: Preferred Term 
V: Verbatim  
S: Start Date (Day)  
E: Stop Date (Day) 
O: Ongoing  
NCI 
CTCAE 
Grade 
SAE? 
 
 
 
 
DLT? 
Causality  
Pa: Patritumab 
Ce: Cetuximab 
Ci: Cisplatin 
Ca: Carboplatin 
Action [a] 
Pa: Patritumab 
Ce: Cetuximab 
Ci: Cisplatin 
Ca: Carboplatin 
Outcome [b] 
Other Action [c] 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/ 
xx/F 
Yes 
 
S: xxxxxxxxxxxxx 
P: xxxxxxxxxxxxx 
V: xxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E:  
O: Yes 
x 
Yes 
Yes 
Related to Pa 
Pa: xx 
Ce: xx 
xx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
S: xxxxxxxxxxxxx 
P: xxxxxxxxxxxxx 
V: xxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E:  
O: Yes 
x 
Yes 
Yes 
Related to Ci 
Pa: xx 
Ce: xx 
xx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
 
S: xxxxxxxxxxxxx 
P: xxxxxxxxxxxxx 
V: xxxxxxxxxxxxx 
S: yyyy-mm-dd (xxx) 
E: yyyy-mm-dd (xxx) 
O: No 
x 
No 
es 
Related to Pa and Ca  
Pa: xx 
Ce: xx 
xx 
O 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/ 
xx/M 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:  [a] Action Taken: N = Dose Not Changed, W = Drug Withdrawn, R = Dose Reduced, INT = Drug Interrupted 
             [b] Outcome: R = Recovered/Resolved, RS = Recovered/Resolved with Sequelae, F =Fatal, NR = Not Recovered/Not Resolved, UNK = Unknown 
             [c] Other Action: N = None, M = Medication Required, H = Hospitalization or prolongation of hospitalization required, O = Other 
 
Source: adam.adae 
Programming Note: continue for HRG Low and Overall on the next page 
                                                                                                  
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 177 of 190 
These Appendices follow Listing 16.2.7.1: 
 
 
Listing 16.2.7.2: Serious Adverse Events, Including Those Leading to Deaths 
Safety Analysis Set 
 
 
Listing 16.2.7.3: Adverse Events Leading to Study Drug Discontinuation 
Safety Analysis Set 
 
 
Listing 16.2.7.4: Adverse Event Leading to Study Drug Interrupti n or Dose Reduction 
Safety Analysis Set 
 
 
Listing 16.2.7.5: Adverse Events o  Interests 
Safety Analysi  Set 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 178 of 190 
Listing 16.2.8.1.1: Laboratory Data – Hematology 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Lab Name 
Parameter 
(Standard Units) 
Visit 
Date/Time 
of Sample 
(Day) 
Result 
[a] 
Normal 
Limits 
Change 
from 
Baseline 
CTC 
Grade 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin/ 
xx/F 
xxxxxxxxxxx 
Test #1 (xxxxx) 
Screening 
yyyy-mm-dd hh:mm (xx)  
xxxx 
xxxx-xxxx 
 
 
 
 
 
CxDx 
yyyy-mm-dd hh:mm (xx)  
xxxx (H) 
xxxx-xxxx 
xxxx 
x 
 
 
 
CxDx 
yyyy-mm-dd hh:mm (xx)  
xxxx 
xxxx-xxxx 
xxxx 
 
 
 
 
CxDx 
yyyy-mm-dd hh:mm (xx)  
xxxx 
xxxx-xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
Test #2 (xxxxx) 
Screening 
yyyy-mm-dd hh:mm (xx)  
xxxx 
xxxx-xxxx 
 
 
 
 
 
CxDx 
yyyy-m
-dd hh:mm (xx)  
xxxx 
xxxx-xxxx 
xxxx 
 
 
 
 
CxDx 
yyyy-mm-dd h:mm (xx)  
xxxx 
xxxx-xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] H = Abnormally High, L = Abnormally Low 
 
Source: adam.adlb 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Daiichi Sankyo Pharma Development                                                                                                                               Page x of y                                                
Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 179 of 190 
These Appendices follow Listing 16.2.8.1.1: 
 
Listing 16.2.8.1.2: Laboratory Data – Chemistry 
Safety Analysis Set 
 
Listing 16.2.8.1.3: Laboratory Data – Urinalysis 
Safety Analysis Set 
 
Programming Notes: Remove Change from baseline and CTC grade columns for urinalysis. 
 
 
Listing 16.2.8.1.4: Laboratory Data – Coagulat on 
Safety Analysis Set 
 
Listing 16.2.8.2.1: Clinically Significant Laboratory Abnormalities or Abnormalities of CTCAE Grade 3 or 4 – Hematology 
Safety Analysis Set 
 
Listing 16.2.8.2.2: Clinically Significant Laboratory Abnormalities or Abnormalities of CTCAE Grade 3 or 4 – Chemistry 
Safety Analysis Set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Listing 16.2.8.2.3 Subjects with Liver Enzymes (ALT, AST) and Total Bilirubin (TBL) Elevation  
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Investigator/ 
Country/Site 
Visit 
Date/Time 
of Sample 
(Day) 
AST 
(xxx-xxx) [a] 
ALT 
(xxx-xxx) [a] 
Total 
 Bilirubin 
(xxx-xxx) [a] 
ALP  
(xxx-xxx) [a] 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + cisplatin 
or carboplatin/ 
xx/F 
xxxxxxxxxxx 
Screening 
yyyy-mm-dd hh:mm (xx)  
xxxx 
xxxx 
xxxx-xxxx 
xxxx 
 
 
 
CxDx 
yyyy-mm-dd hh:mm (xx)  
xxxx (H) 
xxxx (H) 
xxxx-xxxx 
xxxx (H) 
 
 
 
CxDx 
yyyy-mm-dd hh:mm (xx)  
xxxx 
xxxx 
xxxx-xxxx 
xxxx 
 
 
 
CxDx 
yyyy-mm-dd hh:mm (xx)  
xxxx 
xxxx 
xxxx-xxxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] H = Abnormally High, L = Abnormally Low 
 
Source: adam.adlb 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 181 of 190 
Listing 16.2.8.3.1: Vital Signs 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/ 
Gender 
Visit 
Time  Point 
Date of Vital Sign 
Assessment 
(Day) 
Weight 
(kg) 
Pulse Rate 
(beat/min) 
Systolic BP 
(mmHg) 
Diastolic BP 
(mmHg) 
Temperature 
(C) 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/ 
xx/F 
Screening 
 
yyyy-mm-dd (xx) 
xxx.x 
xxx 
xxx 
xxx 
xxx.x 
 
C1D1 
Pre-Infusion 
yyyy-mm-dd (xx) 
xxx.x 
xxx 
xxx 
xxx 
xxx.x 
 
C1D1 
End of Infusion 
yyyy-mm-dd (xx) 
xxx.x 
xxx 
xxx 
xxx 
xxx.x 
 
C1D8 
 
yyyy-mm-dd (xx) 
 
 
 
 
 
 
C1D15 
 
yyyy-mm-dd (xx) 
xxx.x 
xxx 
xxx 
xxx 
xxx.x 
 
CxDx 
 
yyyy-mm-dd (xx) 
xxx.x 
xxx 
xxx 
xxx 
xxx.x 
 
EOT 
 
yyyy-mm-dd (xx) 
xxx x 
xx 
xxx 
xxx 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.advs 
                                                     
Programming note: Time point will be missing for every visit except C1D1. 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 182 of 190 
Listing 16.2.8.3.2: 12-Lead ECG 
Safety Analysis Set 
HRG High 
Subject 
ID/Group/Age/ 
Sex 
Visit 
Date of ECG Assessment 
(Day) 
ECG 
Interpretation 
 
Heart Rate 
(beats/min) 
ECG Intervals (msec) 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/ 
xx/F 
Screening 
yyyy-mm-dd (xx) 
Normal 
xxx 
PR: xx 
RR: xx 
QRS: xxx 
QT: xxx 
QTcB: xxx 
QTcF: xxx 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ 
cetuximab + 
cisplatin or 
carboplatin/ 
xx/M 
Screening 
yyyy-mm-dd (xx) 
Abnormal, not 
clinically significant 
xxx 
PR: xx 
RR: xx 
QRS: xxx 
QT: xxx 
QTcB: xxx 
QTcF: xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QTcB = QTc by Bazett's Correction Formula (msec); QTcF = QTc by Fridericia's Correction Formula (msec) 
 
Source: adam.adeg 
Programming Note: continue for HRG Low and Overall on the next page 
                                        
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Listing 16.2.8.3.3: Physical Examination 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/Gender 
Visit 
Physical Exam Status 
Date of Exam 
(Day) 
 
Body System 
Description of  
Findings 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin/xx/F 
Screening 
No clinically significant findings 
yyyy-mm-dd (xx) 
xxxxxxxxxxxxxxx 
 xxxxxxxxxxxxxxxxxx 
 
 
 
 
xxxxxxxxxxxxxxx 
xxxxxxxxxxxxx 
 
 
 
 
xxxxxxxx xxxxxx 
xxxxxx 
 
 
 
 
xxxxxxxxxx xxxx 
xxxxxxxxxxx 
 
 
 
 
xxxxx xxxxxxxxx 
xxxxxxxxxx 
 
 
 
 
xxxxxxxxxxxxxxx 
xxxxxxxx 
 
 
 
 
xxxxxxxxxxxxxxx 
xxxxxx 
 
 
 
 
 
 
 
CxDx 
Clinically significant changes 
yyyy-mm-dd (xx) 
  
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin/xx/M 
Screening 
No clinically significant findings 
yyyy-mm dd (xx) 
xxxxxxxxxxxxxxx 
 
 
 
 
 
xxxxxxxxxxxxxxx 
 
 
 
 
 
xxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
CxDx 
Not Done 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adpe 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Listing 16.2.8.3.4: Eastern Cooperative Oncology Group (ECOG) Performance Status  
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/Gender 
Visit 
ECOG 
Assessed? 
Date of ECOG 
Assessment (Day) 
ECOG Score [a] 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/xx/F 
Screening 
Yes 
yyyy-mm-dd (xxx) 
x 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab + cetuximab + 
cisplatin or carboplatin 
/xx/M 
Screening 
Yes 
yyyy-mm-dd (xxx) 
x 
 
 
CxDx 
Yes 
yyyy-mm-dd (xxx) 
x 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab + cetuximab + 
cisplatin or carboplatin/xx/F 
Screening 
Yes 
yyyy-mm-dd (xxx) 
x 
 
 
CxDx 
No 
yyyy-mm-dd (xxx) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: [a] 0 = Fully active, able to carry on all pre-disease performance without restriction; 
                 1= Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature;  
                 2 = Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours;  
                 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours;   
                 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair;  
                 5 = Dead. 
 
Source: adam.adqs 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 185 of 190 
Listing 16.2.8.3.5: Echocardiogram 
Safety Analysis Set  
 
HRG High 
Subject ID/ 
Group/Age/Gender 
Visit 
ECHO or MUGA  
Scan Completed? 
Date Procedure Performed 
(Day) 
Type of Assessment 
Left Ventricular Ejection Fraction (LVEF) 
(%) 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin/ 
xx/F 
Screening 
Yes 
yyyy-mm-dd (xx) 
ECHO 
xx.x 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin/ 
xx/M 
Screening 
Yes 
yyyy-mm-dd (xx) 
MUGA 
xx.x 
 
CxDx 
No 
yyyy-mm-dd (xx) 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab 
+ cisplatin or 
carboplatin/ 
xx/F 
Screening 
Yes 
yyyy-mm-dd (xx) 
 
xx.x 
 
CxDx 
Yes 
yyyy mm-dd (xx) 
 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adeg 
Programming Note: continue for HRG Low and Overall on the next page 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 186 of 190 
Listing 16.2.8.4.1: Human Anti-Humanized Antibody (HAHA) 
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/Gender 
Visit 
Time Point 
Date/Time of  
Sample Collection (Day) 
Assay Type 
Screening 
Results 
Confirmatoy 
Results 
Titer  
Results 
Final  
Results 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
C1D1 
xx 
yyyy-mm-dd: hh:mm (xx) 
xxxx 
Negative 
 
 
 
 
CxDx 
xx 
yyyy-mm-dd: hh:mm (xx) 
xxxx 
Nega ive 
 
 
 
 
CxDx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
C1D1 
 
yyyy-mm-dd: hh:mm (xx) 
xxxx 
Negative 
 
 
 
 
CxDx 
 
yyyy-mm-dd: hh:mm (xx) 
xxxx 
Positive 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/ 
xx/F 
C1D1 
 
yyyy-mm-dd: hh:mm (xx) 
xxxx 
Negative 
 
 
 
 
CxDx 
 
yyyy-mm-dd: hh:mm (xx) 
xxxx 
Negative 
 
 
 
 
CxDx 
 
yyyy-mm-dd: hh:mm (xx) 
xxxx 
Negative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  CxDx = Cycle x Day x 
 
Source: adam.adbi  
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 187 of 190 
Listing 16.2.8.4.2: Tumor Tissue Sample Collection and Biomarker Results  
Safety Analysis Set 
 
HRG High 
Subject ID/ 
Group/Age/Gender 
Date of Collection 
( Day) 
Sample ID 
Sample Type 
Biomarker Test  
(Standard Unit) 
Result 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + cisplatin 
or carboplatin/xx/F 
yyyy-mm-dd (xxx) 
xxxxxx 
Fresh Tissue 
Test #1 (xxx) 
xxxx 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + cisplatin 
or carboplatin/xx/M 
yyyy-mm-dd (xxx) 
xxxxxx 
Archived 
Test #1 xxx) 
xxxx 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + cisplatin 
or carboplatin/xx/F 
yyyy-mm-dd (xxx) 
xxxxxx 
Archived 
Tes  #1 xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: adam.adbi 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 188 of 190 
Listing 16.2.9.1.1: FACT-H&N Item Scores 
FACT-H&N Analysis Set 
 
HRG High 
Subject ID/Group/ 
Age/Gender 
Visit 
Date of  
Assessment 
(Study Day) 
Scale 
Item 
 
 
Raw Score 
Imputed Score [a] 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/xx/F 
C1D1 
YYYY-MM-DD  
(xxx) 
HNS 
H&Ni 
x 
 
 
 
 
 
(i=1..12) 
x 
x 
 
 
 
 
 
 
 
 
 
 
EWB 
GE1 
x 
 
 
 
 
 
GE2 
x 
x 
 
 
 
FWB 
GF1 
x 
x 
 
 
 
 
GF2 
x 
 
 
 
 
PWB 
GP1 
x 
x 
 
 
 
 
GP2 
x 
 
 
 
 
SWB 
GS1 
x 
x 
 
 
 
 
GS2 
x 
x 
 
C1D1 
YYYY-MM-DD  
(xxx) 
HNS 
H&Ni 
x 
 
 
 
 
 
H&N2 
x 
 
 
 
 
EWB 
GE1 
x 
 
 
 
 
 
GE2 
x 
 
 
 
 
FWB 
GF1 
x 
x 
 
 
 
 
GF2 
x 
x 
 
 
 
… … 
 
 
 
 
 
Notes: EWB=Emotional Well-Being; FWB=Functional Well-Being; PWB=Physical Well-Being; SWB=Social/Family Well-Being; HNS = Head and Neck 
           Additional Concerns Subscale. 
[a] If fewer than 50% of the raw score are missing on the subscale the raw score is imputed using the mean of the non-missing items. 
Source: adam.adqs 
Programming Note: continue for HRG Low and Overall on the next page 
 
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Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 189 of 190 
Listing 16.2.9.1.2: FACT-H&N Total and Subscale Scores  
FACT-H&N Analysis Set 
 
HRG High 
Subject 
ID/Group/Age/Gender 
Visit 
Date of  
Assessment 
(Study Day) 
PWB 
(# Missing) 
SWB 
(# Missing) 
EWB 
(# Missing) 
FWB 
(# Missing) 
HNS Score 
(# Missing) 
FHNSI Score 
(# Missing) 
FACT-H&N 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or 
carboplatin/xx/F 
C1D1 
YYYY-MM-DD  
(xxx) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx 
 
CxD1 
YYYY-MM-DD  
(xxx) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab + cetuximab + 
cisplatin or carboplatin 
/xx/M 
C1D1 
YYYY-MM-DD  
(xxx) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx  
 
C2D1 
YYYY-MM-DD  
(xxx) 
xx (x) 
x  (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx 
 
 
 
 
 
 
 
 
 
 
xxxxxx/ 
Patritumab + cetuximab + 
cisplatin or 
carboplatin/xx/F 
C1D1 
YYYY-MM-DD  
(xxx) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx 
 
C2D1 
YYYY-MM-D   
(xxx) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx (x) 
xx 
 
CxD1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:  EWB=Emotional Well-Being; FWB=Functional Well-Being; PWB=Physical Well-Being; SWB=Social Well-Being; HNS = Head and Neck 
             Additional Concerns Subscale; FHNSI = Head & Neck Symptom Index;  FACT-H&N total score = PWB + SWB + EWB + FWB + HNS 
 
Source: adam.adqs 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
 
 
 
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Daiichi Sankyo Pharma Development                                                                                                                               Page x of y                                                
Protocol U31287-A-U203                                                                                                                     <progname> <run date time> 
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Page 190 of 190 
Listing 16.2.9.2: EQ-5D Scale Scores 
EQ-5D Analysis Set 
 
HRG High 
Subject ID/Group/ 
Age/Gender 
Visit 
Date of  
Assessment 
(Study Day) 
Item 
Response 
Change from Baseline 
 
 
 
 
 
 
xxxxxx/ 
Patritumab+ cetuximab + 
cisplatin or carboplatin/xx/F 
C1D1 
YYYY-MM-DD  
(xxx) 
1. Mobility 
Not a problem 
 
 
 
 
2. Self-care 
A modera e problem 
x 
 
 
 
3. Usual Activities 
 
 
 
 
 
4.Pain/Discomfort 
 
 
 
 
 
5. Anxiety/Depression 
 
x 
 
 
 
VAS Score 
 
x 
 
 
 
Index Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C1D1 
YYYY-MM-DD  
(xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: EQ-5D descriptive system is coded 1 - 5, with higher core indicating more severe result. 
           The VAS score is numbered from 0 to 100, which 100 means the best health you can imagine, 0 means the worst health you can imagine. 
           Based on the patient’s response to each of the 5 dimensions, a 1-digit number expressing the level selected for that dimension will be recorded and combined in a 5-digit 
number describing the respondent’s health state.  Each of the 5-digit combinations will be converted to a country-specific index value defining the health state of the patient. 
 
Source: adam.adqs 
Programming Note: continue for HRG Low and Overall on the next page 
 
 
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