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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind Phase 2 Study of Palbociclib Plus Cetuximab Versus Cetuximab for the Treatment of Human Papillomavirus-Negative, Cetuximab Naïve Patients With Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck After Failure of One Prior Platinum-Containing Chemotherapy Regimen

    Summary
    EudraCT number
    		 2015-000515-41
    Trial protocol
    		 CZ   HU   ES   PL   SK   IT  
    Global end of trial date
    02 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2023
    First version publication date
    21 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A5481044
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02499120
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this Phase 2 study was to compare the efficacy and safety of palbociclib in combination with cetuximab versus cetuximab in HPV negative, cetuximab naïve subjects with R/M SCCHN after failure of 1 platinum containing regimen.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Japan: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Serbia: 8
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Ukraine: 24
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    125
    EEA total number of subjects
    33
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    88
    From 65 to 84 years
    37
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 125 subjects were randomized; among them, 124 subjects received study treatments. One (1) subject in the palbociclib + cetuximab treatment group was randomized but not treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Palbociclib + Cetuximab
    Arm description
    		 Subjects received Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion followed by 250 mg/m2 weekly infused over 60 minutes.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Palbociclib 125 mg was administered QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Palbociclib 125 mg was administered QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Arm title
    		 Placebo + Cetuximab
    Arm description
    		 Subjects received Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Number of subjects in period 1
    		Palbociclib + Cetuximab Placebo + Cetuximab
    Started
    65
    60
    Received treatment
    64
    60
    Completed
    0
    0
    Not completed
    65
    60
         Adverse event, serious fatal
    52
    43
         Consent withdrawn by subject
    2
    5
         Participant refused further follow-up
    1
    -
         Unspecified
    9
    10
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palbociclib + Cetuximab
    Reporting group description
    		 Subjects received Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Reporting group title
    Placebo + Cetuximab
    Reporting group description
    		 Subjects received Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Reporting group values
    		 Palbociclib + Cetuximab Placebo + Cetuximab Total
    Number of subjects
    		 65 60 125
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 50 38 88
        From 65-84 years
    		 15 22 37
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.3 ( 10.2 ) 60.9 ( 10.1 ) -
    Sex: Female, Male
    Units: Subjects
        FEMALE
    		 8 4 12
        MALE
    		 57 56 113
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    		 47 46 93
        Black|
    		 1 1 2
        Asian|
    		 15 13 28
        Other|
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Palbociclib + Cetuximab
    Reporting group description
    		 Subjects received Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Reporting group title
    Placebo + Cetuximab
    Reporting group description
    		 Subjects received Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death due to any cause. OS (in months) was calculated as (date of death − randomization date +1)/30.4. For subjects lacking survival data beyond the date of their last follow-up, the OS time was censored on the last date they were known to be alive. Subjects lacking survival data beyond randomization had their OS times be censored at randomization. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method. The analysis population was intent-to-treat (ITT) population, which included all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether subjects received study drug or received a different drug from that to which they were randomized.
    End point type
    Primary
    End point timeframe
    Baseline up to primary completion date (PCD) (about 34 months)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    65
    60
    Units: months
        median (confidence interval 95%)
    9.7 (7.3 to 13.9)
    7.8 (6.7 to 10.6)
    Statistical analysis title
    		 Statistical analysis on OS
    Comparison groups
    Palbociclib + Cetuximab v Placebo + Cetuximab
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.18 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.536
         upper limit
    		 1.253
    Notes
    [1] - 1-sided p-value was from the log-rank test stratified by stratification factors ECOG (Eastern Cooperative Oncology Group) per randomization.

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    DR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used. DR was calculated as [the date response ended (ie, date of PD or death) – first CR or PR date + 1)]/30.4. DR was only calculated for the subgroup of all ITT subjects with an objective tumor response.
    End point type
    Secondary
    End point timeframe
    Baseline up to PCD (about 34 months)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    18
    15
    Units: months
        median (confidence interval 95%)
    7.6 (3.7 to 7.7)
    7.4 (3.6 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clinical Benefit Response (CBR)

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    End point title
    		 Percentage of Subjects with Clinical Benefit Response (CBR)
    End point description
    CBR was defined as the overall CR, PR, or stable disease>=24 weeks according to the RECIST version 1.1. Clinical benefit response rate (CBRR) was defined as the proportion of patients with CR, PR, or stable disease>= 24 weeks relative to all randomized patients and randomized patients with measurable disease at baseline. The analysis population was ITT population, which included all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether subjects received study drug or received a different drug from that to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline up to PCD (about 34 months)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    65
    60
    Units: Percentage of subjects
        number (confidence interval 95%)
    36.9 (25.3 to 49.8)
    36.7 (24.6 to 50.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Objective Response (OR)

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    End point title
    		 Percentage of Subjects with Objective Response (OR)
    End point description
    OR was defined as the overall complete response (CR) or partial response (PR) according to the RECIST version 1.1. Objective response rate (ORR) was defined as the proportion of patients with best overall response (BOR) of CR or PR relative to all randomized. The analysis population was ITT population, which included all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether subjects received study drug or received a different drug from that to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline up to PCD (about 34 months)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    65
    60
    Units: Percentage of subjects
        number (confidence interval 95%)
    27.7 (17.3 to 40.2)
    25.0 (14.7 to 37.9)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS which was defined as the time from the date of randomization to the date of the first documentation of objective progression of disease (PD) or death due to any cause, whichever was earlier. Estimates of the PFS curves from the Kaplan Meier method were presented. The analysis population was IT population, which included all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether subjects received study drug or received a different drug from that to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline up to PCD (about 34 months)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    65
    60
    Units: months
        median (confidence interval 95%)
    3.9 (3.6 to 5.6)
    4.6 (2.3 to 5.5)
    Statistical analysis title
    		 Statistical analysis on PFS
    Comparison groups
    Palbociclib + Cetuximab v Placebo + Cetuximab
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4953 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.669
         upper limit
    		 1.495
    Notes
    [2] - 1-sided p-value was from the log-rank test stratified by stratification factors ECOG per randomization.

    Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    TEAEs were defined as adverse events (AEs) which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The analysis population included all subjects who received a t least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.
    End point type
    Secondary
    End point timeframe
    From the first dose through and including 28 calendar days after the last administration of the study treatment (up to 6.9 years)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    64
    60
    Units: subjects
        AEs (all causality)|
    61
    56
        AEs (treatment-related)|
    58
    48
        SAEs (all causality)|
    25
    19
        SAEs (treatment-related)|
    7
    2
        Grade 3 or 4 AEs (all causality)|
    33
    19
        Grade 5 AEs (all causality)|
    15
    11
        Grade 3 or 4 AEs (treatment-related)|
    34
    10
        Grade 5 AEs (treatment-related)|
    1
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
    End point description
    The EORTC QLQ-C30 is a 30 item questionnaire composed of 5 multi-item functional subscales, 3 multi-item symptom scales, a global health/quality of life (QOL) subscale, and 6 single items assessing other cancer related symptoms. The questionnaire employed twenty-eight 4 point Likert scales with responses from “not at all” to “very much” and two 7 point Likert scales for global health and overall QOL. For functional and global QOL scales, higher scores represented a better level of functioning and were converted to a 0 to 100 scale. For symptom oriented scales, a higher score represented more severe symptoms. Negative changes from baseline indicate deterioration in functioning / global QoL scales and improvement in symptom scales. The analysis population included all ITT subjects, who had both baseline and at least 1 follow-up patient reported outcome (PRO) assessment before treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    Baseline up to PCD (about 34 months)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    57
    55
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Global health status / QOL|
    2.819 (-1.49 to 7.13)
    2.687 (-1.70 to 7.08)
        Functional scale: Physical functioning|
    0.736 (-3.26 to 4.73)
    -0.463 (-4.59 to 3.66)
        Functional scale: Role functioning|
    -0.407 (-5.91 to 5.09)
    -1.600 (-7.28 to 4.08)
        Functional scale: Cognitive functioning|
    -1.466 (-5.14 to 2.21)
    -1.230 (-5.06 to 2.59)
        Functional scale: Social functioning|
    1.239 (-4.43 to 6.90)
    2.082 (-3.76 to 7.92)
        Symptom scale/item: Fatigue|
    -2.788 (-7.04 to 1.46)
    -5.124 (-9.50 to -0.75)
        Symptom scale/item: Nausea and vomiting|
    -0.869 (-2.63 to 0.90)
    -1.040 (-2.82 to 0.74)
        Symptom scale/item: Pain|
    -5.977 (-11.06 to -0.90)
    -6.096 (-11.32 to -0.87)
        Symptom scale/item: Dyspnoea|
    3.074 (-2.15 to 8.30)
    5.086 (-0.27 to 10.45)
        Symptom scale/item: Insomnia|
    -4.623 (-10.33 to 1.08)
    -5.018 (-10.88 to 0.84)
        Symptom scale/item: Appetite loss|
    2.247 (-3.89 to 8.38)
    -0.687 (-7.04 to 5.67)
        Symptom scale/item: Constipation|
    -4.120 (-10.30 to 2.06)
    -1.326 (-7.72 to 5.07)
        Symptom scale/item: Diarrhoea|
    4.255 (1.34 to 7.17)
    1.744 (-1.24 to 4.73)
        Symptom scale/item: Financial difficulties|
    -5.258 (-11.61 to 1.10)
    -0.273 (-6.83 to 6.29)
        Functional scale: Emotional functioning|
    4.155 (0.13 to 8.18)
    3.560 (-0.57 to 7.69)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Laboratory Abnormalities

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    End point title
    		 Number of Subjects with Laboratory Abnormalities
    End point description
    The hematology, chemistry and coagulation tests were included in the laboratory examination. Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes. Chemistry evaluation included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, phosphorus or phosphate and hemoglobin A1c (HbA1c). Coagulation evaluation included activated partial thromboplastin time/partial thromboplastin time, international normalized ratio (INR) or prothrombin time. The analysis population included all subjects with at least 1 observation of the laboratory test while on study treatment or during lag time.
    End point type
    Secondary
    End point timeframe
    From the Screening (Day -28) through and including 28 calendar days after the last administration of the study treatment (up to 7 years)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    62
    59
    Units: Subjects
    61
    55
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Organization for Research and Treatment of Cancer Head and Neck Module 35 (EORTC QLQ H&N35)

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    End point title
    		 Change from Baseline in European Organization for Research and Treatment of Cancer Head and Neck Module 35 (EORTC QLQ H&N35)
    End point description
    The EORTC QLQ H&N35 is designed to be used together with the core QLQ C30. The recall period for the items in the module was “the past week”. Items hn1 to hn30 were scored on 4 point Likert type categorical scales (“not at all”, “a little”, “quite a bit”, “very much”). Items hn31 to hn35 had a “no/yes” response format. The scores were transformed into 0 to 100 scales, with a high score implying a high level of symptoms.Negative changes from baseline indicate deterioration in functioning / global QoL scales and improvement in symptom scales. The analysis population included all ITT subjects, who had both baseline and at least 1 follow-up PRO assessment before treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    Baseline up to PCD (about 34 months)
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    57
    55
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Symptom scale/item: Pain|
    -3.565 (-8.56 to 1.43)
    -0.407 (-5.54 to 4.73)
        Symptom scale/item: Swallowing|
    -4.344 (-8.79 to 0.10)
    -1.469 (-6.03 to 3.09)
        Symptom scale/item: Senses problems|
    -1.582 (-7.22 to 4.05)
    -1.879 (-7.72 to 3.96)
        Symptom scale/item: Speech problems|
    -4.541 (-9.21 to 0.13)
    -2.691 (-7.51 to 2.13)
        Symptom scale/item: Trouble with social eating|
    -5.550 (-10.14 to -0.96)
    -0.709 (-5.42 to 4.01)
        Symptom scale/item: Trouble with social contact|
    -1.265 (-5.68 to 3.15)
    3.452 (-1.14 to 8.04)
        Symptom scale/item: Less sexuality|
    -3.323 (-11.44 to 4.80)
    4.904 (-3.72 to 13.53)
        Symptom scale/item: Teeth|
    -1.586 (-8.91 to 5.74)
    -1.880 (-9.29 to 5.53)
        Symptom scale/item: Opening mouth|
    0.347 (-5.29 to 5.99)
    0.215 (-5.56 to 5.99)
        Symptom scale/item: Dry mouth|
    -6.300 (-10.50 to -2.10)
    3.444 (-0.82 to 7.71)
        Symptom scale/item: Sticky saliva|
    -3.912 (-9.70 to 1.88)
    4.680 (-1.22 to 10.58)
        Symptom scale/item: Coughing|
    -3.988 (-8.67 to 0.69)
    -1.717 (-6.48 to 3.04)
        Symptom scale/item: Felt ill|
    1.320 (-4.22 to 6.86)
    0.124 (-5.45 to 5.70)
        Symptom scale/item: Pain killers|
    -13.184 (-24.49 to -1.88)
    -11.393 (-23.02 to 0.24)
        Symptom scale/item: Nutritional supplements|
    0.351 (-7.19 to 7.89)
    -4.370 (-12.23 to 3.49)
        Symptom scale/item: Feeding tube|
    -6.364 (-9.58 to -3.15)
    -0.107 (-3.30 to 3.08)
        Symptom scale/item: Weight loss|
    -17.723 (-27.23 to -8.21)
    -9.470 (-19.16 to 0.22)
        Symptom scale/item: Weight gain|
    -3.030 (-10.08 to 4.02)
    5.159 (-1.96 to 12.27)
    No statistical analyses for this end point

    Secondary: Summary of PFS and OS for P16 Negative (%Positive tumor cells < 70%)

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    End point title
    		 Summary of PFS and OS for P16 Negative (%Positive tumor cells < 70%)
    End point description
    A central test was defined as the tumor tissue-based p16 IHC test performed at a central laboratory (Ventana). The analysis of concordance between HPV status as assessed by local or central laboratory included the number and percentage of subjects with p16 detected or not detected at the central laboratory, given that all local testing must have been negative for HPV in order for the subject to be eligible for the study. Initial analysis of the p16 status was based on the conventional cutoff of 70% p16-positive tumor cells to call out cases that might be considered HPV-positive. P16 expression was scored as positive if strong and diffuse nuclear and cytoplasmic staining was present in at least 70% of the tumor cells. The analysis population included all subjects treated with cetuximab in combination with placebo or palbociclib who had at least 1 baseline biomarker assessment.
    End point type
    Secondary
    End point timeframe
    Screening
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    54
    48
    Units: months
    median (confidence interval 95%)
        PFS|
    3.7 (3.2 to 5.6)
    5.0 (1.3 to 7.2)
        OS|
    9.9 (7.1 to 13.9)
    8.0 (7.0 to 14.7)
    No statistical analyses for this end point

    Secondary: Trough plasma concentration (Ctrough) and within-participant mean steady-state pre-dose concentration (WPM-Ctrough) at steady state for Palbociblib

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    End point title
    		 Trough plasma concentration (Ctrough) and within-participant mean steady-state pre-dose concentration (WPM-Ctrough) at steady state for Palbociblib [3]
    End point description
    Ctrough is steady-state pre-dose concentration, which was observed directly from data. WPM-Ctrough is within-subject mean steady-state pre-dose concentration. For palbociclib, a steady-state trough was to be defined as a pre-dose plasma concentration following at least 7 consecutive days of 125 mg daily dose without dosing interruption and the time window for the PK collection was to be between 24 hr +/- 2 hr and 24 min post-dose the day prior to PK collection and no more than 1 hr post-dose on the day of PK collection. The analysis population included all as-treated subjects, who were treated with the study treatments and had a t least measured plasma concentration for at least 1 analyte (palbociclib and/or cetuximab)
    End point type
    Secondary
    End point timeframe
    Pre-dose of Day 15 in Cycle 1 and Cycle 2
    Notes
    [3] - 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: 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.
    End point values
    		 Palbociclib + Cetuximab
    Number of subjects analysed
    57
    Units: nanograms per millilitre (ng/ml)
    arithmetic mean (standard deviation)
        Ctrough Cycle 1 Day 15|
    69.75 ( 28.208 )
        Ctrough Cycle 2 Day 15|
    67.79 ( 28.905 )
        WPM-Ctrough|
    71.64 ( 30.183 )
    No statistical analyses for this end point

    Secondary: Summary of PFS and OS Based on Investigator Assessment by Rb Expression >= 1%

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    End point title
    		 Summary of PFS and OS Based on Investigator Assessment by Rb Expression >= 1%
    End point description
    Rb expression in the palbociclib and cetuximab treatment group, the relationship of the biomarkers (individually) with PFS and OS were explored using graphical methods such as box plots, at baseline. The tumors of subjects were Rb-positive, which was defined by Rb IHC with>=1% positive tumor cells. The analysis population included all subjects treated with cetuximab in combination with placebo or palbociclib who had at least 1 baseline biomarker assessment.
    End point type
    Secondary
    End point timeframe
    Screening
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    57
    53
    Units: months
    median (confidence interval 95%)
        PFS|
    3.9 (3.5 to 6.2)
    4.6 (2.6 to 5.6)
        OS|
    10.5 (7.1 to 15.6)
    7.8 (6.9 to 11.8)
    No statistical analyses for this end point

    Secondary: Ctrough and Cendinf, WPM-Ctrough and WPM-Cendinf at steady state for Serum Cetuximab

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    End point title
    		 Ctrough and Cendinf, WPM-Ctrough and WPM-Cendinf at steady state for Serum Cetuximab
    End point description
    Ctrough is steady-state pre-dose concentration. Cendinf is steady-state end-of-infusion concentration. Ctrough and Cendinf were observed directly from data. WPM-Ctrough and WPM-Cendinf are within-subject mean steady-state pre-dose concentration and end-of-infusion concentration. Acceptance criteria for a steady-state Cendinf was defined as a PK sample that was 1) collected after at least 3 consecutive weeks of cetuximab IV infusions without interruption or prior dose reduction and 2) was collected at the end of cetuximab infusion time +/- 10% of the actual duration of the cetuximab infusion. The analysis population included all as-treated subjects, who were treated with the study treatments and had at least measured plasma concentration for at least 1 analyte (palbociclib and/or cetuximab)
    End point type
    Secondary
    End point timeframe
    Pre-dose and end-of infusion of Day 15 in Cycle 1 and Cycle 2
    End point values
    		 Palbociclib + Cetuximab Placebo + Cetuximab
    Number of subjects analysed
    57
    57
    Units: ng/ml
    geometric mean (geometric coefficient of variation)
        Ctrough Cycle 1 Day 15|
    39706.407 ( 92 )
    42914.095 ( 62 )
        Ctrough Cycle 2 Day 15|
    54005.307 ( 74 )
    52995.663 ( 71 )
        WPM-Ctrough|
    45605.949 ( 83 )
    46796.538 ( 63 )
        Cendinf Cycle 1 Day 15|
    145748.275 ( 43 )
    137185.479 ( 61 )
        Cendinf Cycle 2 Day 15|
    149155.706 ( 38 )
    153310.061 ( 39 )
        WPM-Cendinf|
    149119.179 ( 36 )
    148063.341 ( 39 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose through and including 28 calendar days after the last administration of the study treatment (up to 6.9 years).
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. An event may be categorized as serious in 1 subject and as non-serious in another subject, or 1 subject may have experienced both a serious and non-serious event during the study. Total number at risk below refers to the number of subjects evaluable for SAEs or AEs.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo + Cetuximab
    Reporting group description
    		 Subjects received Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Reporting group title
    Palbociclib + Cetuximab
    Reporting group description
    		 Subjects received Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute intravenous (IV) infusion followed by 250 mg/m2 weekly infused over 60 minutes.

    Serious adverse events
    		 Placebo + Cetuximab Palbociclib + Cetuximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 60 (31.67%)
    25 / 64 (39.06%)
         number of deaths (all causes)
    43
    52
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    6 / 60 (10.00%)
    7 / 64 (10.94%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Death
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal obstruction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestine perforation
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Cetuximab Palbociclib + Cetuximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 60 (88.33%)
    55 / 64 (85.94%)
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    11 / 64 (17.19%)
         occurrences all number
    0
    26
    Weight decreased
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 64 (7.81%)
         occurrences all number
    6
    5
    Neutrophil count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    9 / 64 (14.06%)
         occurrences all number
    0
    25
    Blood creatinine increased
         subjects affected / exposed
    3 / 60 (5.00%)
    5 / 64 (7.81%)
         occurrences all number
    3
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 64 (3.13%)
         occurrences all number
    7
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 64 (1.56%)
         occurrences all number
    8
    5
    Platelet count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    10 / 64 (15.63%)
         occurrences all number
    0
    21
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 60 (3.33%)
    5 / 64 (7.81%)
         occurrences all number
    4
    5
    Hypotension
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 64 (4.69%)
         occurrences all number
    4
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 60 (8.33%)
    6 / 64 (9.38%)
         occurrences all number
    5
    10
    Dizziness
         subjects affected / exposed
    6 / 60 (10.00%)
    3 / 64 (4.69%)
         occurrences all number
    7
    4
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    0
    12
    Neutropenia
         subjects affected / exposed
    0 / 60 (0.00%)
    19 / 64 (29.69%)
         occurrences all number
    0
    53
    Lymphopenia
         subjects affected / exposed
    1 / 60 (1.67%)
    7 / 64 (10.94%)
         occurrences all number
    1
    22
    Leukopenia
         subjects affected / exposed
    0 / 60 (0.00%)
    13 / 64 (20.31%)
         occurrences all number
    0
    39
    Anaemia
         subjects affected / exposed
    8 / 60 (13.33%)
    23 / 64 (35.94%)
         occurrences all number
    9
    47
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 60 (13.33%)
    9 / 64 (14.06%)
         occurrences all number
    11
    17
    Fatigue
         subjects affected / exposed
    8 / 60 (13.33%)
    8 / 64 (12.50%)
         occurrences all number
    11
    8
    Asthenia
         subjects affected / exposed
    7 / 60 (11.67%)
    5 / 64 (7.81%)
         occurrences all number
    10
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 60 (10.00%)
    8 / 64 (12.50%)
         occurrences all number
    10
    9
    Stomatitis
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    7
    Diarrhoea
         subjects affected / exposed
    5 / 60 (8.33%)
    9 / 64 (14.06%)
         occurrences all number
    12
    11
    Constipation
         subjects affected / exposed
    5 / 60 (8.33%)
    7 / 64 (10.94%)
         occurrences all number
    6
    7
    Vomiting
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 64 (6.25%)
         occurrences all number
    2
    4
    Dysphagia
         subjects affected / exposed
    5 / 60 (8.33%)
    9 / 64 (14.06%)
         occurrences all number
    6
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 64 (4.69%)
         occurrences all number
    5
    4
    Dyspnoea
         subjects affected / exposed
    8 / 60 (13.33%)
    4 / 64 (6.25%)
         occurrences all number
    8
    4
    Productive cough
         subjects affected / exposed
    4 / 60 (6.67%)
    6 / 64 (9.38%)
         occurrences all number
    4
    6
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    13 / 60 (21.67%)
    14 / 64 (21.88%)
         occurrences all number
    22
    23
    Dry skin
         subjects affected / exposed
    2 / 60 (3.33%)
    9 / 64 (14.06%)
         occurrences all number
    2
    12
    Pruritus
         subjects affected / exposed
    4 / 60 (6.67%)
    7 / 64 (10.94%)
         occurrences all number
    5
    11
    Rash
         subjects affected / exposed
    21 / 60 (35.00%)
    27 / 64 (42.19%)
         occurrences all number
    35
    42
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    4 / 60 (6.67%)
    5 / 64 (7.81%)
         occurrences all number
    4
    8
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 60 (10.00%)
    4 / 64 (6.25%)
         occurrences all number
    6
    4
    Paronychia
         subjects affected / exposed
    8 / 60 (13.33%)
    2 / 64 (3.13%)
         occurrences all number
    8
    3
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 64 (6.25%)
         occurrences all number
    5
    4
    Hypomagnesaemia
         subjects affected / exposed
    8 / 60 (13.33%)
    11 / 64 (17.19%)
         occurrences all number
    10
    25
    Hypokalaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    6 / 64 (9.38%)
         occurrences all number
    1
    7
    Hypocalcaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    6 / 64 (9.38%)
         occurrences all number
    1
    8
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Hyperglycaemia
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 64 (4.69%)
         occurrences all number
    10
    3
    Decreased appetite
         subjects affected / exposed
    10 / 60 (16.67%)
    12 / 64 (18.75%)
         occurrences all number
    10
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2015
    1. Protocol Summary/Study Design/ Tumor Assessment Requirements Flowchart/Sections 3 Study Design, 7.1.1.2 Post-Baseline Tumor Assessments: Removed statement concerning continuous treatment beyond RECIST-defined disease progression (agreement between Sponsor and FDA). 2. Protocol Summary, Study Design/Section 3 Study Design/Section 4.3 Randomization Criteria/Section 5.1 Allocation to Treatment/9.2.1 Analysis of Primary Endpoint: Clarified stratification terminology from checkpoint inhibitors to immunotherapy. 3. Schedule of Activities/Tumor Assessment Requirements Flowchart/Sections 7.1.1.1 Screening/Baseline Tumor Assessments and 7.1.1.2 Post-Baseline Tumor Assessments: Added CT or MRI scan of the chest and abdomen (including the liver) to support PFS secondary endpoint. 4. Clarification of Inclusion Criteria # 9 for patients aged 20 years old or greater as applicable by local country regulations. 5. Section 5.5.3.1.1 Cetuximab Hypersensitivity Reactions: Simplified wording for cetuximab retreatment after Grade 2 hypersensitivity reactions. 6. Section 5.5.3.1.4 Cetuximab Gastrointestinal Adverse Events: Added “Patients experiencing treatment-related Grade 4 vomiting or diarrhea should have their cetuximab and palbociclib/placebo treatments permanently discontinued.” 7. Section 5.5.3.2.1 Palbociclib/Placebo Dosing Interruptions/Delays: Added “Patients experiencing treatment-related Grade 4 vomiting, diarrhea, or hypertension should have their palbociclib/placebo and cetuximab treatments permanently discontinued.” Removed “≥” from Grade 3 non-hematologic bullet point (5th bullet point). Added bullet point “Grade 4 non-hematologic toxicities (see exceptions of vomiting, diarrhea, or hypertension above).” 8. Required Protocol Template updates in Adverse Event Reporting section and Communication of Results by Pfizer section.
    31 Mar 2016
    1. Schedule of Activities/Tumor Assessment Requirements Flowchart: 29Jul2015 PCL removal of the phrase "on Day 1 of event cycles" for Disease Assessment to align with Section 7.1.1, Tumor Assessment. 2. Schedule of Activities, footnote c/Section 6.2, Active Treatment Phase: Add vital signs for any new cycle Day 1 procedures. 3. Schedule of Activities, footnote l/Section 6.3, End of Treatment Visit/Section 7.3.1, Laboratory Safety Assessments: included patients starting post-study anticancer therapy for 8 week chemistry panel analysis. 4. Schedule of Activities, footnote n /Abbreviations/Section 7.3.1, Laboratory Safety Assessments: 21Oct2015 PCL added aPTT as acceptable coagulation parameter. 5. Schedule of Activities, footnote y/Section 5.8, Concomitant Treatments: Added further clarification for patients beginning new therapy before the 28-day time period is complete. 6. Schedule of Activities, footnote z/Section 7.7, Patient Reported Outcomes: Added further clarification for patients starting post-study anticancer therapy. 7. Tumor Assessment Requirements Flowchart, footnote d/Section 7.1.1 Tumor Assessment: Removed the phrase “and pelvis”. 8. Section 4.2 Exclusion Criteria: Removed the phrase “or requirement for a feeding tube” and clarified inability to swallow capsules for Exclusion Criterion # 5.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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