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Clinical Trial Results:
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Weekly Doses of Palifermin (Recombinant Human Keratinocyte Growth Factor, rHuKGF) for the Reduction of Oral Mucositis in Subjects With Advanced Head and Neck Cancer ReceivingAdjuvant Radiotherapy and Chemotherapy (RT/CT)

Summary
EudraCT number	2004-002016-28
Trial protocol	DE GB AT IT ES
Global end of trial date	11 Jul 2016

Results information
Results version number	v1(current)
This version publication date	26 Jul 2017
First version publication date	26 Jul 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

20040118

ISRCTN number

US NCT number

NCT00131638

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Jul 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 Jul 2016

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to evaluate the efficacy of palifermin administered weekly at the dose of 120 μg/kg intravenously (IV) in reducing the incidence of severe (World Health Organization [WHO] grade 3 or 4) oral mucositis (OM) in subjects with locally advanced head and neck cancer (HNC) receiving radiotherapy with concurrent chemotherapy as an adjuvant treatment for their disease (postoperative setting).

Protection of trial subjects

This study was conducted in accordance with the principles that have their origin in the Declaration of Helsinki and in compliance with Food and Drug Administration (FDA), the Canadian Health Protection Branch (HPB), and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals. An independent data monitoring committee of oncologists and a statistician reviewed safety and efficacy data according to a prespecified schedule.

Background therapy

Conventional or three-dimensional radiation planning techniques and standard fractionation (5 × 2.0 Gy/wk) were followed. The total dose was 60 Gy or 66 Gy (allowable range, ± 15%) after R0 or R1 resection, respectively. Spinal cord dose was restricted to 48 Gy. The radiation volume included the tumor bed with a 2 to 3 cm safety margin and regional nodal areas. Radiation breaks were not allowed and were considered to be a major deviation when 5 or more consecutive days or 10 or more total treatment days were missed. Cisplatin 100 mg/m² was given intravenously on days 1 and 22 after appropriate hydration. Patients irradiated beyond week 6 (boost or catch-up radiation) received an additional 100 mg/m² cisplatin (day 43). Local supportive care, including normal saline rinses, topical anesthetics, feeding tubes, and hematopoietic growth factors were allowed according to each center's procedures.

Evidence for comparator

Actual start date of recruitment

27 Jan 2005

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

10 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 62

Country: Number of subjects enrolled

Spain: 36

Country: Number of subjects enrolled

France: 36

Country: Number of subjects enrolled

Italy: 32

Country: Number of subjects enrolled

Austria: 30

Country: Number of subjects enrolled

Australia: 15

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

Canada: 4

Worldwide total number of subjects

224

EEA total number of subjects

205

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

184

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were enrolled between January 27, 2005, and August 17, 2007 at 38 study centers in Germany, Spain, France, Italy, Austria, Australia, the United Kingdom, and Canada.

Screening details

The original protocol included 3 treatment groups randomized in a 1:1:1 ratio: placebo, 7-dose palifermin and 4-dose palifermin. Protocol Amendment 3 removed the 4-dose palifermin group. Subjects were stratified by postsurgical residual tumor stage (R0 versus R1) and anatomical tumor location (oral cavity/oropharynx versus hypopharynx/larynx).

Period 1 title

Oral Mucositis Evaluation Phase (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received a single dose of placebo administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Administered by bolus intravenous injection

Palifermin 4-dose

Arm description

Participants received a single dose of 120 μg/kg palifermin administered intravenously 3 days before the start of radiotherapy, and 3 once-weekly doses during a 6-week course of radio/chemotherapy. This treatment group was removed with implementation of protocol amendment 3.

Arm type

Experimental

Investigational medicinal product name

Palifermin

Investigational medicinal product code

Other name

Kepivance®

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Administered by bolus intravenous injection

Palifermin 7-dose

Arm description

Participants received a single dose of 120 μg/kg palifermin administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Arm type

Experimental

Investigational medicinal product name

Palifermin

Investigational medicinal product code

Other name

Kepivance®

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intravenous bolus use

Dosage and administration details

Administered by bolus intravenous injection

Number of subjects in period 1	Placebo	Palifermin 4-dose	Palifermin 7-dose
Started	94	38	92
Received Study Drug	93	38	92
Completed	82	34	79
Not completed	12	4	13
Consent withdrawn by subject	4	1	2
Administrative decision	-	-	1
Other	2	1	5
Death	-	1	1
Adverse event	5	-	3
Lost to follow-up	1	-	1
Ineligibility determined	-	1	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received a single dose of placebo administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Reporting group title

Palifermin 4-dose

Reporting group description

Reporting group title

Palifermin 7-dose

Reporting group description

Participants received a single dose of 120 μg/kg palifermin administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Reporting group values	Placebo	Palifermin 4-dose	Palifermin 7-dose	Total
Number of subjects	94	38	92	224
Age Categorical
Units: Subjects
Adults (18-64 years)	73	33	78	184
From 65-84 years	21	5	14	40
Age Continuous
Units: years
arithmetic mean (standard deviation)	56.7 ± 8.7	54.2 ± 8.7	56.3 ± 8.4	-
Gender Categorical
Units: Subjects
Female	19	5	14	38
Male	75	33	78	186
Race
Units: Subjects
Caucasian	94	38	91	223
Asian	0	0	1	1
Distribution of Subjects by Randomization Strata
Stratification factors for randomization were: postsurgical residual tumor: no residual tumor (R0) versus microscopic residual tumor only (R1) and Anatomical tumor location: oral cavity / oropharynx versus hypopharynx / larynx).
Units: Subjects
R0 - oral cavity or oropharynx	47	19	46	112
R0 - hypopharynx or larynx	14	6	15	35
R1 - oral cavity or oropharynx	25	10	25	60
R1 - hypopharynx or larynx	8	3	6	17

End points

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Reporting group title

Placebo

Reporting group description

Participants received a single dose of placebo administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Reporting group title

Palifermin 4-dose

Reporting group description

Reporting group title

Palifermin 7-dose

Reporting group description

Participants received a single dose of 120 μg/kg palifermin administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Subject analysis set title

Palifermin 7-dose

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received a single dose of 120 μg/kg administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy. Includes 1 participant randomized to placebo who received 1 dose of palifermin in error.

Subject analysis set title

Overall Palifermin

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received a single dose of 120 μg/kg administered intravenously 3 days before the start of radiotherapy, and 3 or 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Primary: Percentage of Participants with Severe Oral Mucositis

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End point title

Percentage of Participants with Severe Oral Mucositis

End point description

Oral mucositis (OM) was assessed twice a week during the radio/chemotherapy period. Severity was assessed according to the World Health Organization (WHO) criteria: Grade 1: may include buccal mucosal scalloping with or without erythema. No ulcers. Patient can swallow solid diet. Grade 2: must include ulcers with or without erythema. Patient can swallow solid diet. Grade 3: must include ulcers with or without (extensive) erythema. Patient is able to swallow liquid, but not solid diet. Grade 4: mucositis to the extent that alimentation is not possible. Participants with at least one OM assessment with a grade of 3 or 4 during the evaluation period were considered to have had an incidence of severe OM; partiipants with no post-randomization oral mucositis assessments were assumed to have severe oral mucositis. This endpoint was assessed using the full analysis set which included all randomized participants.

End point type

Primary

End point timeframe

The Acute Oral Mucositis Evaluation Phase was defined as lasting from the date of randomization through Week 12 (or up to Week 15 if OM was not resolved to ≤ WHO Grade 2 by Week 12).

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	94	38	92
Units: percentage of participants
number (not applicable)	66	68	51

Analysis of Incidence of Severe Oral Mucositis

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0269 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Proportions

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

-0.02

Notes
[1] - Generalized Cochran-Mantel-Haenszel test for general association stratified by post surgical residual tumor stage and anatomical tumor location.

Secondary: Duration of Severe Oral Mucositis

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End point title

Duration of Severe Oral Mucositis

End point description

Duration of severe OM was calculated as the number of days from the onset of severe OM (first grade 3 or 4 OM) to the day when severe OM was resolved (first time grade 2 or less was observed after last grade 3 or 4). Participants who did not experience severe OM were assigned a duration of severe OM of 0 days. Participants with no post-randomization oral mucositis assessments were assumed to have severe oral mucositis with an assumed duration equal to the grand mean of all participants experiencing the event.

End point type

Secondary

End point timeframe

Mucositis was assessed 2 times weekly throughout RT/CT, and then until severe mucositis returned to grade ≤ 2 or until week 15. Thereafter, subjects with OM WHO ≥ Grade 2 were assessed once weekly until OM resolved to WHO Grade ≤ 1, or until week 24.

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	94	38	92
Units: days
arithmetic mean (standard deviation)	22.6 ± 22.2	20.3 ± 19.5	17.9 ± 25.9

Analysis of Duration of Severe Oral Mucositis

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.1871 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Mean Duration

Point estimate

-4.68

Confidence interval

level

95%

sides

2-sided

lower limit

-11.34

upper limit

1.98

Notes
[2] - The type I error for the secondary efficacy endpoints was controlled using the Hochberg procedure.
[3] - Generalized Cochran-Mantel-Haenszel test for mean score difference stratified by post surgical residual tumor stage and anatomical tumor location.

Secondary: Average Patient-reported Mouth and Throat Soreness Score

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End point title

Average Patient-reported Mouth and Throat Soreness Score

End point description

The Oral Mucositis Weekly Questionnaire for Head and Neck Cancer (OMWQ-HN) is a 12 item questionnaire administered to participants twice weekly. The mouth and throat soreness (MTS) score was calculated from Question 3 “How much mouth and throat soreness did you experience in the past 24 hours?” answered on a scale from 0 (no soreness) to 4 (extreme soreness). For each participant an average patient-reported mouth and throat soreness score was calculated by dividing the sum of the MTS scores at each assessment by the total number of assessments possible. This endpoint was assessed using the Patient Reported Outcomes (PRO) evaluable subset which included all randomized participants with a valid baseline assessment for MTS question 3 of the OMWQ-HN and at least 1 completed assessment each week for MTS up to withdrawal or the end of study week 7, or ≥ 70% overall compliance for MTS until withdrawal or the end of study week 7.

End point type

Secondary

End point timeframe

Acute Oral Mucositis Evaluation Phase

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	83	32	84
Units: units on a scale
arithmetic mean (standard deviation)	1.57 ± 0.63	1.51 ± 0.57	1.52 ± 0.69

Analysis of Mouth and Throat Soreness Score

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.789 ^[5]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Means

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.16

Notes
[4] - The type I error for the secondary efficacy endpoints was controlled using the Hochberg procedure.
[5] - Generalized Cochran-Mantel-Haenszel test for mean score difference using modified ridit score stratified by post surgical residual tumor stage and anatomical tumor location.

Secondary: Time to Onset of Severe Oral Mucositis

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End point title

Time to Onset of Severe Oral Mucositis

End point description

Time to onset of severe oral mucositis was calculated as the number of days from randomization to date of first onset of severe (WHO grade 3 or 4) OM using the Kaplan-Meier procedure. Participants without an assessed event by the end of the acute OM evaluation phase were censored at the date of last assessment for OM. If the end of the OM evaluation phase assessment had not occurred the last OM assessment date was used as the censoring date. "99999" indicates data not estimable.

End point type

Secondary

End point timeframe

The Acute Oral Mucositis Evaluation Phase was defined as lasting from the date of subject randomization through Week 12 (or up to Week 15 if OM is not resolved to ≤ WHO Grade 2 by Week 12).

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	94	38	92
Units: days
median (inter-quartile range (Q1-Q3))	32 (22 to 99999)	36 (26 to 99999)	45 (28 to 99999)

Analysis of Time to Onset of Severe Oral Mucositis

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.1535 ^[7]

Method

Stratified Log Rank Test

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.44

upper limit

0.95

Notes
[6] - The type I error for the secondary efficacy endpoints was controlled using the Hochberg procedure.
[7] - Log rank test stratified by post surgical residual tumor stage and anatomical tumor location.

Secondary: Total Dose of Opioid Analgesic Used

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End point title

Total Dose of Opioid Analgesic Used

End point description

The total dose of opioid analgesics was the sum of all opioid analgesic administrations converted to intravenous (IV) morphine equivalents. Participants withdrawing before the first dose of study drug were assumed to have used opioid analgesics, and to have a total dose equal to the grand median of all participants using opioid analgesics. This endpoint was assessed using the full analysis set.

End point type

Secondary

End point timeframe

Acute Oral Mucositis Evaluation Phase

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	94	38	92
Units: mg of IV morphine equivalents
median (inter-quartile range (Q1-Q3))	171.23 (0 to 1100.21)	61.17 (0 to 354.27)	60.8 (0 to 837.5)

Analysis of Total Dose of Opioid Analgesic Used

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.789 ^[9]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Mean Total Dose

Point estimate

146.95

Confidence interval

level

95%

sides

2-sided

lower limit

-250.75

upper limit

544.64

Notes
[8] - The type I error for the secondary efficacy endpoints was controlled using the Hochberg procedure.
[9] - Generalized Cochran-Mantel-Haenszel test for mean score difference using modified ridit score stratified by post surgical residual tumor stage and anatomical tumor location.

Secondary: Percentage of Participants with Breaks In Radiotherapy of ≥ 5 Consecutive Fractions of Scheduled Radiotherapy

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End point title

Percentage of Participants with Breaks In Radiotherapy of ≥ 5 Consecutive Fractions of Scheduled Radiotherapy

End point description

Participants who missed 5 or more consecutive fractions of planned radiotherapy or who discontinued radiotherapy prior to completion of planned radiotherapy were considered to have an unplanned break in radiotherapy. This endpoint was assessed using the full analysis set.

End point type

Secondary

End point timeframe

6 weeks

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	94	38	92
Units: percentage of participants
number (not applicable)	14	21	15

Analysis of Breaks in Radiotherapy

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.789 ^[11]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Proportions

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.11

Notes
[10] - The type I error for the secondary efficacy endpoints was controlled using the Hochberg procedure.
[11] - Generalized Cochran-Mantel-Haenszel test for general association stratified by post surgical residual tumor stage and anatomical tumor location.

Secondary: Percentage of Participants with Unplanned Delays in Chemotherapy for Cisplatin Administration

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End point title

Percentage of Participants with Unplanned Delays in Chemotherapy for Cisplatin Administration

End point description

An unplanned delay in chemotherapy for cisplatin administration was defined as day 22 chemotherapy administered on day 25 or later (i.e. 3 or more days delay), or no chemotherapy dose scheduled for day 22 at all. This endpoint was assessed using the full analysis set.

End point type

Secondary

End point timeframe

6 weeks

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	94	38	92
Units: percentage of participants
number (not applicable)	40	37	30

Analysis of Delays in Cisplatin Administration

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.6543 ^[13]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Proportions

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.24

upper limit

0.04

Notes
[12] - The type I error for the secondary efficacy endpoints was controlled using the Hochberg procedure.
[13] - Generalized Cochran-Mantel-Haenszel test for general association stratified by post surgical residual tumor stage and anatomical tumor location.

Secondary: Percentage of Participants with Xerostomia at the Month 4 Visit

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End point title

Percentage of Participants with Xerostomia at the Month 4 Visit

End point description

Xerostomia is an abnormal dryness of mouth. Dry mouth/xerostomia was assessed using weighted saliva volume determination and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, where Grade 1 = Symptomatic (dry or thick saliva) without significant dietary alteration; Unstimulated saliva flow > 0.2 ml/min. Grade 2 = Symptomatic and significant oral intake alteration (eg, copious water, other lubricants, diet limited to purees and/or soft, moist foods); Unstimulated saliva 0.1 to 0.2 ml/min. Grade 3 = Symptoms leading to inability to adequately aliment orally; IV fluids, tube feedings, or total parenteral nutrition indicated; Unstimulated saliva < 1 ml/min. Participants with a grade of 2 or higher CTCAE xerostomia assessment at the month 4 visit were considered to have had xerostomia. This endpoint was assessed using the full analysis set. Participants with no month 4 xerostomia assessment results were assumed to have xerostomia grade ≥ 2.

End point type

Secondary

End point timeframe

Month 4

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	94	38	92
Units: percentage of participants
number (not applicable)	35	47	43

Analysis of Incidence of Xerostomia

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

186

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

= 0.1871 ^[15]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in Proportions

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.27

Notes
[14] - The type I error for the secondary efficacy endpoints was controlled using the Hochberg procedure.
[15] - Generalized Cochran-Mantel-Haenszel test for general association stratified by post surgical residual tumor stage anatomical and tumor location.

Secondary: Number of Participants with Adverse Events

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End point title

Number of Participants with Adverse Events ^[16]

End point description

The severity of adverse events (AEs) was graded according to CTCAE version 3. The possible relationship of each AE to study drug was assessed by the investigator. Serious adverse events include, but were not be limited to any event that - was fatal - was life threatening - required in-patient hospitalization or prolongation of existing hospitalization - was a persistent or significant disability/incapacity - was a congenital anomaly/birth defect. A protocol-specific limiting toxicity (PSLT) was defined as any grade ≥ 3 AE considered related to study drug that prompted discontinuation of study drug. This endpoint was analyzed using the safety subset which included all participants who were randomized and received at least one dose of study drug, with participants analyzed according to the treatment they actually received. One participant randomized to placebo received one dose of palifermin and is included in the Palifermin 7-dose group for safety endpoints.

End point type

Secondary

End point timeframe

From first dose of study drug until the end of the acute oral mucositis evaluation phase (up to 15 weeks).

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	92	38	93
Units: participants
Any adverse event	89	35	91
Serious adverse events	41	18	31
Severe adverse events (CTCAE grade 3, 4, or 5)	51	23	46
Treatment-related adverse events	10	11	27
Treatment-related serious adverse events	0	3	1
Severe treatment-related adverse events	0	4	6
Leading to discontinuation from study	5	0	3
Leading to discontinuation of study drug	5	2	11
Protocol-specific limiting toxicity	0	0	4
On-study deaths	1	1	1

No statistical analyses for this end point

Secondary: Number of Participants who Developed Anti-palifermin Antibodies

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End point title

Number of Participants who Developed Anti-palifermin Antibodies ^[17]

End point description

The antibody testing utilized a tiered assay approach. Samples were first screened for anti-palifermin binding antibodies in a validated electrochemiluminescence (ECL) based immunoassay. If the immunoassay yielded any positive samples, they were tested in a validated cell-based bioassay to test for neutralizing antibodies to palifermin. If a sample was positive in both assays, the participant was defined as positive for neutralizing antibodies. This endpoint was analyzed in the safety subset; participants who received palifermin were combined in the analysis.

End point type

Secondary

End point timeframe

Samples for antibody testing were collected at baseline and weeks 4, 8 and 12.

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Palifermin dose groups were combined for antibody analyses.

End point values	Placebo	Overall Palifermin
Number of subjects analysed	91	132
Units: participants
Binding antibody positive	5	7
Neutralizing antibody positive	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Disease Progression at Week 12

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End point title

Number of Participants with Disease Progression at Week 12 ^[18]

End point description

Disease progression is the recurrence of tumor post-surgery in the anatomical region of the primary tumor (ie within the radiation field) or distant metastases. Disease progression was analyzed in the safety population.

End point type

Secondary

End point timeframe

Week 12

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose
Number of subjects analysed	92	38	93
Units: participants	1	0	6

No statistical analyses for this end point

Secondary: Overall Survival

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End point title

Overall Survival ^[19]

End point description

Overall survival was analyzed using Kaplan-Meier methods and was defined as the time from the date of first dose of study drug to the date of death, regardless of cause. Participants who did not die were censored at the date the participant was last known to be alive. Overall survival was analyzed in the safety subset. "99999" indicates data not estimable.

End point type

Secondary

End point timeframe

From randomization until the final analysis data cut-off date of 11 July 2016. The median duration of follow-up was 70.2 months in the placebo group and 58.8 months in the overall palifermin group.

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose	Overall Palifermin
Number of subjects analysed	92	38	93	131
Units: months
median (confidence interval 95%)	112 (81.8 to 99999)	99999 (58.3 to 99999)	109.2 (61.5 to 99999)	114.2 (71.8 to 99999)

Analysis of Overall Survival

Comparison groups

Placebo v Overall Palifermin

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.943 ^[20]

Method

Stratified Cox Proportional Hazards

Parameter type

Hazard ratio (HR)

Point estimate

0.985

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

1.492

Notes
[20] - The Cox proportional hazard model is stratified by disease stage (III vs. IV) and anatomical tumor location (oral cavity or oropharynx vs. nasopharynx vs. hypopharynx or larynx).

Analysis of Overall Survival

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7 ^[21]

Method

Stratified Cox Proportional Hazards

Parameter type

Hazard ratio (HR)

Point estimate

1.091

Confidence interval

level

95%

sides

2-sided

lower limit

0.701

upper limit

1.698

Notes
[21] - The Cox proportional hazard model is stratified by disease stage (III vs. IV) and anatomical tumor location (oral cavity or oropharynx vs. nasopharynx vs. hypopharynx or larynx)

Secondary: Time to Disease Progression

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End point title

Time to Disease Progression ^[22]

End point description

Disease progression is the recurrence of tumor post-surgery in the anatomical region of the primary tumor (ie within the radiation field) or distant metastases. Time to disease progression was analyzed using Kaplan-Meier methods and was defined as the time from randomization to the date when disease progression was determined. Participants with no assessment of disease progression were censored at the date of last disease assessment. If a participant who had evidence of complete response (at least one assessment indicating complete response) died without evidence of tumor progression, the date of death was used as the censoring date. Time to disease progression was analyzed in the safety subset. "99999" indicates data not estimable.

End point type

Secondary

End point timeframe

From randomization until the final analysis data cut-off date of 11 July 2016. The median duration of follow-up was 70.2 months in the placebo group and 58.8 months in the overall palifermin group.

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose	Overall Palifermin
Number of subjects analysed	92	38	93	131
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (117.8 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Progression-Free Survival

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End point title

Progression-Free Survival ^[23]

End point description

Progression free survival (PFS) was analyzed using Kaplan-Meier methods and was defined as the time between the date of first dose of study drug and the date of physical or radiological evidence of disease progression or death (regardless of cause). Participants who were still alive without disease progression were censored at the date of last disease response assessment. If the participant did not have a disease response assessment, then the date the participant was last known to be alive was used as the censoring date. Progression-free survival was analyzed in the safety subset. "99999" indicates data not estimable.

End point type

Secondary

End point timeframe

From randomization until the final analysis data cut-off date of 11 July 2016. The median duration of follow-up was 70.2 months in the placebo group and 58.8 months in the overall palifermin group.

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose	Overall Palifermin
Number of subjects analysed	92	38	93	131
Units: months
median (confidence interval 95%)	88.5 (52.7 to 99999)	99999 (56.2 to 99999)	109.2 (43.4 to 99999)	109.2 (62.6 to 99999)

Analysis of Progression-free Survival

Comparison groups

Placebo v Overall Palifermin

Number of subjects included in analysis

223

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.555 ^[24]

Method

Stratified Cox Proportional Hazards

Parameter type

Hazard ratio (HR)

Point estimate

0.889

Confidence interval

level

95%

sides

2-sided

lower limit

0.601

upper limit

1.315

Notes
[24] - The Cox proportional hazard model is stratified by disease stage (III vs. IV) and anatomical tumor location (oral cavity or oropharynx vs. nasopharynx vs. hypopharynx or larynx)

Analysis of Progression-free Survival

Comparison groups

Placebo v Palifermin 7-dose

Number of subjects included in analysis

185

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.948 ^[25]

Method

Stratified Cox Proportional Hazards

Parameter type

Hazard ratio (HR)

Point estimate

0.986

Confidence interval

level

95%

sides

2-sided

lower limit

0.648

upper limit

1.5

Notes
[25] - The Cox proportional hazard model is stratified by disease stage (III vs. IV) and anatomical tumor location (oral cavity or oropharynx vs. nasopharynx vs. hypopharynx or larynx)

Secondary: Number of Participants with Second Primary Tumors

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End point title

Number of Participants with Second Primary Tumors ^[26]

End point description

End point type

Secondary

End point timeframe

From first dose of study drug until the final analysis data cut-off date of 11 July 2016. The median duration of follow-up was 70.2 months in the placebo group and 58.8 months in the overall palifermin group.

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose	Overall Palifermin
Number of subjects analysed	92	38	93	131
Units: participants	7	6	8	14

No statistical analyses for this end point

Secondary: Number of Participants with Other Malignancies

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End point title

Number of Participants with Other Malignancies ^[27]

End point description

End point type

Secondary

End point timeframe

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose	Overall Palifermin
Number of subjects analysed	92	38	93	131
Units: participants	9	4	8	12

No statistical analyses for this end point

Secondary: Number of Participants with Leukoplakia

Top of page

End point title

Number of Participants with Leukoplakia ^[28]

End point description

End point type

Secondary

End point timeframe

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are reported for the safety subset

End point values	Placebo	Palifermin 4-dose	Palifermin 7-dose	Overall Palifermin
Number of subjects analysed	92	38	93	131
Units: participants	1	0	4	4

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From first dose of study drug until the end of the acute oral mucositis evaluation phase (up to 15 weeks).

Adverse event reporting additional description

The safety subset includes all participants who were randomized and received at least one dose of investigational product, with subjects analyzed according to the treatment they actually received. One participant randomized to placebo received one dose of palifermin in error and is included in the Palifermin 7-dose group for safety.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

9.0

Reporting group title

Placebo

Reporting group description

Participants received a single dose of placebo administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Reporting group title

Palifermin 7-dose

Reporting group description

Participants received a single dose of 120 μg/kg administered intravenously 3 days before the start of radiotherapy, and 6 once-weekly doses during a 6-week course of radio/chemotherapy.

Reporting group title

Palifermin 4-dose

Reporting group description

Serious adverse events	Placebo	Palifermin 7-dose	Palifermin 4-dose
Total subjects affected by serious adverse events
subjects affected / exposed	41 / 92 (44.57%)	31 / 93 (33.33%)	18 / 38 (47.37%)
number of deaths (all causes)	1	1	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to lymph nodes
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngeal neoplasm
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 92 (0.00%)	2 / 93 (2.15%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Tracheostomy
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Face oedema
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	3 / 92 (3.26%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	10 / 92 (10.87%)	4 / 93 (4.30%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 92 (2.17%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 92 (2.17%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngeal fistula
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngolaryngeal pain
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 92 (1.09%)	4 / 93 (4.30%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	2 / 92 (2.17%)	1 / 93 (1.08%)	2 / 38 (5.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural fistula
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radiation associated pain
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radiation mucositis
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Nervous system disorders
Convulsion
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 92 (2.17%)	1 / 93 (1.08%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 2	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	2 / 92 (2.17%)	2 / 93 (2.15%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 92 (1.09%)	1 / 93 (1.08%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 92 (0.00%)	2 / 93 (2.15%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	3 / 92 (3.26%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	3 / 92 (3.26%)	7 / 93 (7.53%)	5 / 38 (13.16%)
occurrences causally related to treatment / all	0 / 3	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	8 / 92 (8.70%)	1 / 93 (1.08%)	2 / 38 (5.26%)
occurrences causally related to treatment / all	0 / 9	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal perforation
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oral pain
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	4 / 92 (4.35%)	0 / 93 (0.00%)	3 / 38 (7.89%)
occurrences causally related to treatment / all	0 / 4	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	7 / 92 (7.61%)	2 / 93 (2.15%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 8	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin necrosis
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute prerenal failure
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	1 / 92 (1.09%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 92 (2.17%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	1 / 92 (1.09%)	3 / 93 (3.23%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure chronic
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in jaw
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess jaw
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess of salivary gland
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Candidiasis
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridial infection
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	3 / 92 (3.26%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 92 (2.17%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Superinfection oral
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	3 / 92 (3.26%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cachexia
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	6 / 92 (6.52%)	4 / 93 (4.30%)	3 / 38 (7.89%)
occurrences causally related to treatment / all	0 / 6	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 92 (0.00%)	0 / 93 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 92 (1.09%)	1 / 93 (1.08%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Palifermin 7-dose	Palifermin 4-dose
Total subjects affected by non serious adverse events
subjects affected / exposed	85 / 92 (92.39%)	84 / 93 (90.32%)	34 / 38 (89.47%)
Vascular disorders
Flushing
subjects affected / exposed	2 / 92 (2.17%)	2 / 93 (2.15%)	2 / 38 (5.26%)
occurrences all number	2	3	2
Hypertension
subjects affected / exposed	2 / 92 (2.17%)	3 / 93 (3.23%)	2 / 38 (5.26%)
occurrences all number	2	4	2
Hypotension
subjects affected / exposed	1 / 92 (1.09%)	1 / 93 (1.08%)	2 / 38 (5.26%)
occurrences all number	1	1	2
Lymphoedema
subjects affected / exposed	2 / 92 (2.17%)	2 / 93 (2.15%)	3 / 38 (7.89%)
occurrences all number	3	3	3
General disorders and administration site conditions
Asthenia
subjects affected / exposed	7 / 92 (7.61%)	12 / 93 (12.90%)	3 / 38 (7.89%)
occurrences all number	9	12	3
Face oedema
subjects affected / exposed	5 / 92 (5.43%)	9 / 93 (9.68%)	3 / 38 (7.89%)
occurrences all number	5	13	3
Fatigue
subjects affected / exposed	13 / 92 (14.13%)	6 / 93 (6.45%)	0 / 38 (0.00%)
occurrences all number	17	7	0
General physical health deterioration
subjects affected / exposed	1 / 92 (1.09%)	0 / 93 (0.00%)	2 / 38 (5.26%)
occurrences all number	1	0	3
Localised oedema
subjects affected / exposed	2 / 92 (2.17%)	5 / 93 (5.38%)	0 / 38 (0.00%)
occurrences all number	2	10	0
Oedema peripheral
subjects affected / exposed	3 / 92 (3.26%)	5 / 93 (5.38%)	2 / 38 (5.26%)
occurrences all number	3	8	2
Pyrexia
subjects affected / exposed	14 / 92 (15.22%)	13 / 93 (13.98%)	3 / 38 (7.89%)
occurrences all number	16	15	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	6 / 92 (6.52%)	10 / 93 (10.75%)	1 / 38 (2.63%)
occurrences all number	6	11	1
Dysphonia
subjects affected / exposed	11 / 92 (11.96%)	10 / 93 (10.75%)	4 / 38 (10.53%)
occurrences all number	20	18	7
Dyspnoea
subjects affected / exposed	2 / 92 (2.17%)	6 / 93 (6.45%)	1 / 38 (2.63%)
occurrences all number	2	6	1
Hiccups
subjects affected / exposed	3 / 92 (3.26%)	5 / 93 (5.38%)	0 / 38 (0.00%)
occurrences all number	3	5	0
Pharyngolaryngeal pain
subjects affected / exposed	5 / 92 (5.43%)	6 / 93 (6.45%)	2 / 38 (5.26%)
occurrences all number	6	6	2
Psychiatric disorders
Insomnia
subjects affected / exposed	12 / 92 (13.04%)	5 / 93 (5.38%)	1 / 38 (2.63%)
occurrences all number	13	5	1
Investigations
Blood creatinine increased
subjects affected / exposed	5 / 92 (5.43%)	5 / 93 (5.38%)	1 / 38 (2.63%)
occurrences all number	5	5	1
Weight decreased
subjects affected / exposed	10 / 92 (10.87%)	14 / 93 (15.05%)	6 / 38 (15.79%)
occurrences all number	16	19	7
Injury, poisoning and procedural complications
Radiation skin injury
subjects affected / exposed	17 / 92 (18.48%)	17 / 93 (18.28%)	5 / 38 (13.16%)
occurrences all number	31	34	13
Nervous system disorders
Dizziness
subjects affected / exposed	6 / 92 (6.52%)	5 / 93 (5.38%)	0 / 38 (0.00%)
occurrences all number	6	9	0
Dysgeusia
subjects affected / exposed	6 / 92 (6.52%)	6 / 93 (6.45%)	3 / 38 (7.89%)
occurrences all number	6	8	5
Headache
subjects affected / exposed	4 / 92 (4.35%)	9 / 93 (9.68%)	3 / 38 (7.89%)
occurrences all number	8	9	3
Lethargy
subjects affected / exposed	1 / 92 (1.09%)	3 / 93 (3.23%)	2 / 38 (5.26%)
occurrences all number	1	3	2
Paraesthesia
subjects affected / exposed	1 / 92 (1.09%)	1 / 93 (1.08%)	4 / 38 (10.53%)
occurrences all number	1	3	4
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	12 / 92 (13.04%)	9 / 93 (9.68%)	2 / 38 (5.26%)
occurrences all number	16	12	3
Leukopenia
subjects affected / exposed	18 / 92 (19.57%)	11 / 93 (11.83%)	12 / 38 (31.58%)
occurrences all number	25	15	16
Neutropenia
subjects affected / exposed	12 / 92 (13.04%)	14 / 93 (15.05%)	5 / 38 (13.16%)
occurrences all number	13	17	6
Thrombocytopenia
subjects affected / exposed	2 / 92 (2.17%)	5 / 93 (5.38%)	1 / 38 (2.63%)
occurrences all number	2	6	1
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	7 / 92 (7.61%)	7 / 93 (7.53%)	3 / 38 (7.89%)
occurrences all number	7	8	3
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 92 (2.17%)	5 / 93 (5.38%)	1 / 38 (2.63%)
occurrences all number	2	6	1
Constipation
subjects affected / exposed	23 / 92 (25.00%)	21 / 93 (22.58%)	13 / 38 (34.21%)
occurrences all number	27	25	14
Diarrhoea
subjects affected / exposed	5 / 92 (5.43%)	10 / 93 (10.75%)	3 / 38 (7.89%)
occurrences all number	5	10	3
Dry mouth
subjects affected / exposed	2 / 92 (2.17%)	5 / 93 (5.38%)	1 / 38 (2.63%)
occurrences all number	2	6	1
Dysphagia
subjects affected / exposed	18 / 92 (19.57%)	32 / 93 (34.41%)	9 / 38 (23.68%)
occurrences all number	30	54	22
Nausea
subjects affected / exposed	44 / 92 (47.83%)	43 / 93 (46.24%)	16 / 38 (42.11%)
occurrences all number	78	63	29
Odynophagia
subjects affected / exposed	12 / 92 (13.04%)	8 / 93 (8.60%)	0 / 38 (0.00%)
occurrences all number	13	8	0
Oedema mouth
subjects affected / exposed	3 / 92 (3.26%)	5 / 93 (5.38%)	0 / 38 (0.00%)
occurrences all number	3	6	0
Vomiting
subjects affected / exposed	32 / 92 (34.78%)	32 / 93 (34.41%)	12 / 38 (31.58%)
occurrences all number	51	47	17
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	3 / 92 (3.26%)	3 / 93 (3.23%)	3 / 38 (7.89%)
occurrences all number	3	3	3
Dermatitis
subjects affected / exposed	8 / 92 (8.70%)	7 / 93 (7.53%)	4 / 38 (10.53%)
occurrences all number	13	8	6
Erythema
subjects affected / exposed	8 / 92 (8.70%)	11 / 93 (11.83%)	2 / 38 (5.26%)
occurrences all number	11	19	2
Periorbital oedema
subjects affected / exposed	0 / 92 (0.00%)	1 / 93 (1.08%)	2 / 38 (5.26%)
occurrences all number	0	1	2
Pruritus
subjects affected / exposed	2 / 92 (2.17%)	4 / 93 (4.30%)	4 / 38 (10.53%)
occurrences all number	2	6	4
Swelling face
subjects affected / exposed	2 / 92 (2.17%)	5 / 93 (5.38%)	0 / 38 (0.00%)
occurrences all number	2	5	0
Renal and urinary disorders
Renal impairment
subjects affected / exposed	1 / 92 (1.09%)	1 / 93 (1.08%)	2 / 38 (5.26%)
occurrences all number	1	1	3
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 92 (1.09%)	6 / 93 (6.45%)	0 / 38 (0.00%)
occurrences all number	1	8	0
Infections and infestations
Candidiasis
subjects affected / exposed	7 / 92 (7.61%)	9 / 93 (9.68%)	3 / 38 (7.89%)
occurrences all number	7	10	3
Fungal infection
subjects affected / exposed	4 / 92 (4.35%)	1 / 93 (1.08%)	2 / 38 (5.26%)
occurrences all number	4	1	2
Oral candidiasis
subjects affected / exposed	23 / 92 (25.00%)	21 / 93 (22.58%)	7 / 38 (18.42%)
occurrences all number	24	26	9
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	14 / 92 (15.22%)	14 / 93 (15.05%)	3 / 38 (7.89%)
occurrences all number	15	14	4
Dehydration
subjects affected / exposed	8 / 92 (8.70%)	2 / 93 (2.15%)	1 / 38 (2.63%)
occurrences all number	10	3	2
Hyperuricaemia
subjects affected / exposed	3 / 92 (3.26%)	5 / 93 (5.38%)	2 / 38 (5.26%)
occurrences all number	5	8	4
Hypokalaemia
subjects affected / exposed	7 / 92 (7.61%)	6 / 93 (6.45%)	4 / 38 (10.53%)
occurrences all number	8	7	5

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Were there any global substantial amendments to the protocol? Yes

28 Feb 2005

Changes included: • In the chemoradiotherapy treatment regimen used in this study, cisplatin is administered as a radiosensitizer before RT on days 1, 22, and 43. Study investigators agreed that in this setting cisplatin should only be administered in association with RT. Therefore, only subjects scheduled to receive the optional “boost radiation” during week 7 were to receive cisplatin on day 43. Study procedures were clarified to reflect this. • The Performance Status Scale for HNC patients, Attitudes questionnaire and Clinical Symptoms questionnaires were removed from the study because these instruments were not deemed to provide data that would further support the objective of the study. In addition, 2 questions originally left out from the FACT-HN in error have been added, because they are a fundamental component of this PRO tool. • The exclusion criteria were amended to allow for the inclusion of subjects with curatively treated in situ cervical cancer, or basal cell carcinoma of the skin without evidence of disease for > 3 years. • As an additional safety measure, vital sign measurements were added immediately before the first dose of investigational product and within 1 hour after the first dose. • Documentation of socioeconomic status was added to review the possible correlation between socioeconomic status and disease outcome. • Pharmacy instructions were amended to include language on protection of study drug from light.

16 May 2005

Originally the main objective of this study was to evaluate the efficacy and safety of multiple weekly administrations of palifermin at the dose of 180 μg/kg to patients with advanced HNC receiving adjuvant RT/CT. However, following an independent DMC review of available safety data from subjects who received the 180 μg/kg dose in the setting of adjuvant RT with concomitant CT (including the first 7 subjects enrolled in this study) the DMC recommended to reduce the dose to 120 μg/kg weekly for this study in patients with advanced HNC postsurgery.

14 Feb 2006

• The original design compared two active treatment groups (“palifermin once weekly x 7”; “palifermin once weekly x 4”) to placebo. The preferred dosing regimen was “palifermin once weekly x 7” based on the assumption that dosing throughout the entire duration of RT offered the optimal benefit to this population. In order to obtain robust efficacy data in a timely manner, Amgen decided to focus on the evaluation of this treatment group compared to placebo (90 subjects per arm, 180 subjects in total). Therefore, the protocol was amended throughout to reflect removal of the 4-dose arm. • The number of patients required for the interim futility analysis for efficacy was amended to reflect the reduction in sample size. • Clarification was provided for study drug administered after week 7. • Clarification of secondary endpoints relating to incidence of delays in RT and CT was made.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Severe Oral Mucositis

Primary: Percentage of Participants with Severe Oral Mucositis

Secondary: Duration of Severe Oral Mucositis

Secondary: Duration of Severe Oral Mucositis

Secondary: Average Patient-reported Mouth and Throat Soreness Score

Secondary: Average Patient-reported Mouth and Throat Soreness Score

Secondary: Time to Onset of Severe Oral Mucositis

Secondary: Time to Onset of Severe Oral Mucositis

Secondary: Total Dose of Opioid Analgesic Used

Secondary: Total Dose of Opioid Analgesic Used

Secondary: Percentage of Participants with Breaks In Radiotherapy of ≥ 5 Consecutive Fractions of Scheduled Radiotherapy

Secondary: Percentage of Participants with Breaks In Radiotherapy of ≥ 5 Consecutive Fractions of Scheduled Radiotherapy

Secondary: Percentage of Participants with Unplanned Delays in Chemotherapy for Cisplatin Administration

Secondary: Percentage of Participants with Unplanned Delays in Chemotherapy for Cisplatin Administration

Secondary: Percentage of Participants with Xerostomia at the Month 4 Visit

Secondary: Percentage of Participants with Xerostomia at the Month 4 Visit

Secondary: Number of Participants with Adverse Events

Secondary: Number of Participants with Adverse Events

Secondary: Number of Participants who Developed Anti-palifermin Antibodies

Secondary: Number of Participants who Developed Anti-palifermin Antibodies

Secondary: Number of Participants with Disease Progression at Week 12

Secondary: Number of Participants with Disease Progression at Week 12

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Time to Disease Progression

Secondary: Time to Disease Progression

Secondary: Progression-Free Survival

Secondary: Progression-Free Survival

Secondary: Number of Participants with Second Primary Tumors

Secondary: Number of Participants with Second Primary Tumors

Secondary: Number of Participants with Other Malignancies

Secondary: Number of Participants with Other Malignancies

Secondary: Number of Participants with Leukoplakia

Secondary: Number of Participants with Leukoplakia

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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