Trial Outcomes & Findings for Open-Label Trial Of Oral PF-00299804 By Continuous Dosing In Patients With Recurrent Or Metastatic Head And Neck Squamous Cell Cancer (NCT NCT00768664)

NCT ID: NCT00768664

Last Updated: 2021-02-09

Results Overview

Percentage of participants with best OR of confirmed CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST) relative to total number of evaluable participants for response. CR defined as disappearance of all target/non-target lesions. PR defined as at least a 30 percent (%) decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions. Confirmed responses (CR and PR) were those that persisted on a follow-up imaging assessment greater than or equal to (≥)4 weeks after the initial objective documentation of response.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 69 participants
• Primary outcome timeframe: Baseline up to 18 months
• Results posted on: 2021-02-09

Participant Flow

Participant milestones

Measure	Dacomitinib 45 mg Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Overall Study STARTED	69
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	69

Reasons for withdrawal

Measure	Dacomitinib 45 mg Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Overall Study Death	57
Overall Study Lost to Follow-up	2
Overall Study Other	9
Overall Study Participant refused	1

Baseline Characteristics

Open-Label Trial Of Oral PF-00299804 By Continuous Dosing In Patients With Recurrent Or Metastatic Head And Neck Squamous Cell Cancer

Baseline characteristics by cohort

Measure	Dacomitinib 45 mg n=69 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Age, Continuous	61.9 years STANDARD_DEVIATION 9.0 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	61 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to 18 months

Population: Response-Evaluable Population: All participants with measurable disease (per RECIST), treated, with baseline and ≥1 on-study assessment. Participants who discontinued early before on-study tumor assessment due to PD were evaluable, but not if discontinued early due to reasons such as participant request, lack of compliance, or early toxicity.

Percentage of participants with best OR of confirmed CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST) relative to total number of evaluable participants for response. CR defined as disappearance of all target/non-target lesions. PR defined as at least a 30 percent (%) decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions. Confirmed responses (CR and PR) were those that persisted on a follow-up imaging assessment greater than or equal to (≥)4 weeks after the initial objective documentation of response.

Outcome measures

Measure

Dacomitinib 45 mg n=63 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Percentage of Participants With Objective Response (OR) of Complete Response (CR) or Partial Response (PR)

12.5 Percentage of participants Interval 5.6 to 23.5

SECONDARY outcome

Timeframe: Baseline up to 18 months

Population: Response Evaluable population; n equals (=) number of participants with an objective response of CR or PR.

Time in weeks from the first documentation of objective tumor response (CR or PR) to progression or death due to progressive disease (PD). DR was calculated as (the date of the first documentation of PD or death due to PD minus the date of the first CR or PR that was subsequently confirmed plus 1). DR was calculated for the subgroup of participants with a confirmed objective tumor response (CR or PR).

Outcome measures

Measure

Dacomitinib 45 mg n=8 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Duration of Response (DR)

17.9 weeks Interval 12.6 to 20.1

SECONDARY outcome

Timeframe: Baseline up to 18 months

Population: Response Evaluable population; n=number of participants with a best overall response of SD.

Time in weeks from start of treatment to date of objective disease progression (based on RECIST criteria). SD defined as neither sufficient shrinkage for PR nor sufficient increase for PD, taking as a reference the smallest sum of the longest dimensions since treatment start. Participants last known to be alive, not to have started new anticancer treatment, to be progression free, and who had a baseline and at least 1 on-study disease assessment were censored at date of last objective disease assessment that verified lack of PD. Participants who died not due to PD censored on death date.

Outcome measures

Measure

Dacomitinib 45 mg n=36 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Duration of Stable Disease (SD)

14.6 weeks Interval 12.0 to 24.7

SECONDARY outcome

Timeframe: Baseline up to 18 months

Population: ITT Population: all enrolled participants.

Time in weeks from date of enrollment to first documentation of PD, death due to any cause, symptomatic deterioration, or start of secondary anticancer therapy, whichever occurred first. PFS calculated as (first event date minus enrollment date plus 1). Documentation of progression determined from objective disease assessment based on RECIST criteria. PD defined as at least a 20% increase in the sum of the longest dimensions of the target lesions taking as a reference the smallest sum of the longest dimensions recorded since treatment started or the appearance of 1 or more new lesions.

Outcome measures

Measure

Dacomitinib 45 mg n=69 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Progression-Free Survival (PFS)

12.1 weeks Interval 11.1 to 17.9

SECONDARY outcome

Timeframe: Baseline up to 52 weeks

Population: ITT Population

Probability of being event-free (event defined as PD, death due to any cause, symptomatic deterioration, or start of secondary anticancer therapy) at 26 weeks and 52 weeks after the first dose of study treatment.

Outcome measures

Measure	Dacomitinib 45 mg n=69 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Progression-Free Survival (PFS) at 6 Months and at 1 Year Probability of being event free at Week 26	21.4 percent chance of being event free Interval 11.4 to 33.4
Progression-Free Survival (PFS) at 6 Months and at 1 Year Probability of being event free at Week 52	2.1 percent chance of being event free Interval 0.2 to 9.8

SECONDARY outcome

Timeframe: Baseline up to 18 months

Population: ITT Population

Time in weeks from the start date of enrollment to date of death due to any cause. OS was calculated as (the death date minus the enrollment date plus 1). Participants without death dates, last known to be alive were censored at last contact.

Outcome measures

Measure

Dacomitinib 45 mg n=69 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Overall Survival (OS)

34.6 weeks Interval 29.4 to 52.1

SECONDARY outcome

Timeframe: Baseline up to Week 52

Population: ITT Population

Probability of survival 26 weeks and 52 weeks after the first dose of study treatment.

Outcome measures

Measure	Dacomitinib 45 mg n=69 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Overall Survival at 6 Months and 1 Year Survival Probability at Week 26	66.5 percent chance of survival Interval 53.7 to 76.5
Overall Survival at 6 Months and 1 Year Survival Probability at Week 52	39.6 percent chance of survival Interval 27.6 to 51.3

SECONDARY outcome

Timeframe: Predose on Day 1 of Cycles 2, 3, and 4 and predose on Day 8 of Cycle 1

Population: Pharmacokinetic (PK) population: all enrolled participants who received at least 1 dose of study medication from whom at least 1 PK sample was obtained. Here, "Overall number of participants analyzed" signifies participants evaluable for this outcome measure and "number analyzed" signifies participants evaluable for specific rows.

Trough concentrations of dacomitinib in plasma measured as nanograms per milliliter (ng/mL).

Outcome measures

Measure	Dacomitinib 45 mg n=63 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Trough Plasma Concentrations (Ctrough) of Dacomitinib After Repeat Dosing Cycle 1 Day 8	64.30 ng/mL Interval 0.0 to 118.0
Trough Plasma Concentrations (Ctrough) of Dacomitinib After Repeat Dosing Cycle 2 Day 1	76.85 ng/mL Interval 7.67 to 244.0
Trough Plasma Concentrations (Ctrough) of Dacomitinib After Repeat Dosing Cycle 3 Day 1	74.50 ng/mL Interval 21.6 to 248.0
Trough Plasma Concentrations (Ctrough) of Dacomitinib After Repeat Dosing Cycle 4 Day 1	69.60 ng/mL Interval 12.1 to 191.0

SECONDARY outcome

Timeframe: Predose on Day 1 of Cycles 2, 3, and 4 and predose on Day 8 of Cycle 1

Population: PK population: all enrolled participants who received at least 1 dose of study medication from whom at least 1 PK sample was obtained. Here, "Overall number of participants analyzed" signifies participants evaluable for this outcome measure and "number analyzed" signifies participants evaluable for specific rows.

Outcome measures

Measure	Dacomitinib 45 mg n=7 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Ctrough of Dacomitinib After Repeat Dosing In Participants Requiring Administration of Dacomitinib With a Feeding Tube Cycle 1 Day 8	81.30 ng/mL Interval 46.1 to 105.0
Ctrough of Dacomitinib After Repeat Dosing In Participants Requiring Administration of Dacomitinib With a Feeding Tube Cycle 2 Day 1	92.05 ng/mL Interval 64.3 to 130.0
Ctrough of Dacomitinib After Repeat Dosing In Participants Requiring Administration of Dacomitinib With a Feeding Tube Cycle 3 Day 1	129.2 ng/mL Interval 95.3 to 163.0
Ctrough of Dacomitinib After Repeat Dosing In Participants Requiring Administration of Dacomitinib With a Feeding Tube Cycle 4 Day 1	156 ng/mL Interval 156.0 to 156.0

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at predose and 1, 2, 4, 6, 8, 10, and 24 hours postdose

Population: PK Population; n=number of participants requiring administration of dacomitinib with a feeding tube.

Outcome measures

Measure

Dacomitinib 45 mg n=1 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Maximum Observed Plasma Concentration (Cmax) In Participants Requiring Administration of Dacomitinib With a Feeding Tube

23.80 ng/mL Interval 23.8 to 23.8

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at predose and 1, 2, 4, 6, 8, 10, and 24 hours postdose

Population: PK Population; n=number of participants requiring administration of dacomitinib with a feeding tube.

Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).

Outcome measures

Measure

Dacomitinib 45 mg n=1 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) In Participants Requiring Administration of Dacomitinib With a Feeding Tube

285.0 ng*hour (hr)/mL Interval 285.0 to 285.0

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at predose and 1, 2, 4, 6, 8, 10, and 24 hours postdose

Population: PK Population; n=number of participants requiring administration of dacomitinib with a feeding tube.

Outcome measures

Measure

Dacomitinib 45 mg n=1 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Time to Reach Maximum Observed Plasma Concentration (Tmax) In Participants Requiring Administration of Dacomitinib With a Feeding Tube

4.00 hours Interval 4.0 to 4.0

SECONDARY outcome

Timeframe: Cycle 1 Day 1 at predose and 1, 2, 4, 6, 8, 10, and 24 hours postdose

Population: PK Population; n=number of participants requiring administration of dacomitinib with a feeding tube.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Outcome measures

Measure

Dacomitinib 45 mg n=1 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.

Plasma Decay Half-Life (t1/2)

NA hours Insufficient sampling to determine plasma half-life

SECONDARY outcome

Timeframe: Baseline up to 18 months

Population: Biomarker analysis set: all enrolled participants who had baseline samples submitted as per Institutional Review Board/Independent Ethics Committee approval and participant consent. Here, "number analyzed" signifies participants evaluable at specific rows.

The best overall response was best response recorded from the start of the treatment until disease progression/recurrence. In this outcome measure, biomarkers status and best overall response was reported in terms of correlation coefficient.

Outcome measures

Measure	Dacomitinib 45 mg n=48 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Correlation Between Biomarkers Status and Best Overall Response HPV Overall Status	0.799 Correlation coefficient
Correlation Between Biomarkers Status and Best Overall Response EGFR VIII Status with DNA Method	1.000 Correlation coefficient
Correlation Between Biomarkers Status and Best Overall Response PTEN:	0.840 Correlation coefficient
Correlation Between Biomarkers Status and Best Overall Response Mutation	1.000 Correlation coefficient

SECONDARY outcome

Timeframe: Baseline up to 18 Months

Population: Biomarker analysis set: all enrolled participants who had baseline samples submitted as per Institutional Review Board/Independent Ethics Committee approval and participant consent. Here, "Overall number of participants analyzed" signifies participants evaluable for this outcome measures and "number analyzed" signifies participants evaluable at specific rows.

H-score is a measure of the immunohistochemistry staining positivity. The range for H-score is between 0 and 300. A higher score refers to stronger staining of a particular marker.

Outcome measures

Measure	Dacomitinib 45 mg n=13 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: MET: at baseline	66.3 Score on a scale Standard Deviation 71.26
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: MET: at Cycle 1 Day 8	53.9 Score on a scale Standard Deviation 57.83
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: HER3: at baseline	12.2 Score on a scale Standard Deviation 27.29
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: HER3: at Cycle 1 Day 8	9.6 Score on a scale Standard Deviation 16.09
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: AKT: at baseline	99.1 Score on a scale Standard Deviation 77.90
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: AKT: at Cycle 1 Day 8	123.8 Score on a scale Standard Deviation 77.83
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: CC3: at baseline	22.1 Score on a scale Standard Deviation 28.86
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: CC3: at Cycle 1 Day 8	17.9 Score on a scale Standard Deviation 27.41
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: EGFR: at baseline	190.4 Score on a scale Standard Deviation 113.11
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: EGFR: at Cycle 1 Day 8	184.4 Score on a scale Standard Deviation 113.01
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: ERK: at baseline	148.1 Score on a scale Standard Deviation 74.26
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: ERK: at Cycle 1 Day 8	126.5 Score on a scale Standard Deviation 63.80
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: HER2: at baseline	36.8 Score on a scale Standard Deviation 52.60
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: HER2: at Cycle 1 Day 8	43.0 Score on a scale Standard Deviation 49.51
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: HER3: at baseline	60.6 Score on a scale Standard Deviation 62.49
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: HER3: at Cycle 1 Day 8	50.2 Score on a scale Standard Deviation 42.41
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pEGFR: at baseline	101.2 Score on a scale Standard Deviation 72.01
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pEGFR: at Cycle 1 Day 8	115.6 Score on a scale Standard Deviation 56.35
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pEGFR: ratio to baseline	1.0 Score on a scale Standard Deviation 0.47
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: MET: at baseline	70.0 Score on a scale Standard Deviation 37.31
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: MET: at Cycle 1 Day 8	81.6 Score on a scale Standard Deviation 54.84
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pAKT: at baseline	41.9 Score on a scale Standard Deviation 51.71
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pAKT: at Cycle 1 Day 8	31.4 Score on a scale Standard Deviation 54.78
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pERK: at baseline	103.3 Score on a scale Standard Deviation 46.36
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pERK: at Cycle 1 Day 8	88.3 Score on a scale Standard Deviation 41.51
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pHER2: at baseline	81.6 Score on a scale Standard Deviation 31.79
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pHER2: at Cycle 1 Day 8	78.5 Score on a scale Standard Deviation 39.37
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pMET: at baseline	0.0 Score on a scale Standard Deviation 0.00
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Cytoplasm: pMET: at Cycle 1 Day 8	0.0 Score on a scale Standard Deviation 0.00
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: EGFR: at baseline	258.3 Score on a scale Standard Deviation 60.41
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: EGFR: at Cycle 1 Day 8	209.4 Score on a scale Standard Deviation 99.88
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: HER2: at baseline	8.2 Score on a scale Standard Deviation 24.01
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: HER2: at Cycle 1 Day 8	4.3 Score on a scale Standard Deviation 8.58
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: pEGFR: at baseline	5.8 Score on a scale Standard Deviation 14.27
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: pEGFR: at Cycle 1 Day 8	4.5 Score on a scale Standard Deviation 7.27
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane pHER2: at baseline	1.6 Score on a scale Standard Deviation 2.57
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane pHER2: at Cycle 1 Day 8	5.8 Score on a scale Standard Deviation 9.28
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: pMET: at baseline	0.0 Score on a scale Standard Deviation 0.00
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Membrane: pMET: at Cycle 1 Day 8	0.0 Score on a scale Standard Deviation 0.00
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: AKT: at baseline	87.5 Score on a scale Standard Deviation 67.31
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: AKT: at Cycle 1 Day 8	111.8 Score on a scale Standard Deviation 72.93
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: ERK: at baseline	152.3 Score on a scale Standard Deviation 95.93
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: ERK: at Cycle 1 Day 8	117.5 Score on a scale Standard Deviation 73.69
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: pAKT: at baseline	40.6 Score on a scale Standard Deviation 53.37
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: pAKT: at Cycle 1 Day 8	19.1 Score on a scale Standard Deviation 38.07
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: pERK: at baseline	152.7 Score on a scale Standard Deviation 88.08
H-Score at Baseline and Post-baseline for Paired Biopsy Biomarkers Nucleus: pERK: at Cycle 1 Day 8	144.8 Score on a scale Standard Deviation 76.57

SECONDARY outcome

Timeframe: Baseline up to 18 Months

Population: Biomarker analysis set: all enrolled participants who had baseline samples submitted as per Institutional Review Board/Independent Ethics Committee approval and participant consent. Here, "Overall number of participants analyzed" signifies participants evaluable for this outcome measures and "number analyzed" signifies participants evaluable at specific rows.

H-score is a measure of the immunohistochemistry staining positivity. The range for H-score is between 0 and 300. A higher score refers to stronger staining of a particular marker.

Outcome measures

Measure	Dacomitinib 45 mg n=13 Participants Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: AKT	2.0 Ratio Standard Deviation 3.03
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: CC3	1.0 Ratio Standard Deviation 0.63
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: EGFR	1.0 Ratio Standard Deviation 0.17
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: ERK	0.9 Ratio Standard Deviation 0.29
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: HER2	0.7 Ratio Standard Deviation 0.50
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: HER3	0.7 Ratio Standard Deviation 0.60
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: pEGFR	1.0 Ratio Standard Deviation 0.47
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: MET	1.2 Ratio Standard Deviation 0.44
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: pAKT	0.3 Ratio Standard Deviation 0.28
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: pERK	0.9 Ratio Standard Deviation 0.35
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Cytoplasm: pHER2	0.8 Ratio Standard Deviation 0.42
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Membrane: EGFR	0.8 Ratio Standard Deviation 0.33
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Membrane: HER2	0.3 Ratio Standard Deviation NA Standard deviation could not be calculated due to 1 participant.
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Membrane: HER3	0.6 Ratio Standard Deviation 0.50
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Membrane: MET	0.8 Ratio Standard Deviation 0.41
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Membrane: pEGFR	2.5 Ratio Standard Deviation 4.33
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Membrane pHER2	4.3 Ratio Standard Deviation 4.50
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Nucleus: AKT	2.8 Ratio Standard Deviation 4.73
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Nucleus: ERK	1.1 Ratio Standard Deviation 1.38
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Nucleus: pAKT	0.3 Ratio Standard Deviation 0.59
H-Score at Ratio to Baseline for Paired Biopsy Biomarkers Nucleus: pERK	0.9 Ratio Standard Deviation 0.33

Adverse Events

Dacomitinib 45 mg

Serious events: 20 serious events

Other events: 68 other events

Deaths: 0 deaths

Serious adverse events

Measure	Dacomitinib 45 mg n=69 participants at risk Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Blood and lymphatic system disorders Anaemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Angina pectoris	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Atrial fibrillation	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardio-respiratory arrest	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dysphagia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Vomiting	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Chest pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Disease progression	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Brain abscess	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Cellulitis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Pneumonia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Sepsis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Septic shock	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Pelvic fracture	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Blood creatinine increased	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Decreased appetite	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Dehydration	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypercalcaemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperglycaemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyponatraemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Cerebral infarction	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Motor dysfunction	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Urinary retention	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Laryngeal oedema	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pneumothorax	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Respiratory disorder	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Other adverse events

Measure	Dacomitinib 45 mg n=69 participants at risk Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) received dacomitinib 45 milligram (mg) tablets, orally, once daily (QD) continuously until unacceptable toxicity, disease progression, withdrawal of consent, or death. There were no planned treatment breaks, each cycle was defined as 21 days for the purposes of scheduling. Dose reductions (in 15 mg increments) to a minimum of 15 mg QD were allowed; dose re-escalations were not allowed.
Blood and lymphatic system disorders Anaemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Atrial flutter	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Left ventricular dysfunction	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Pericardial effusion	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Deafness	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Hearing impaired	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Endocrine disorders Hypothyroidism	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Blepharitis	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Conjunctival irritation	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Conjunctivitis	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Dry eye	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Entropion	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Eye discharge	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Eye irritation	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Eye oedema	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Eye pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Eye pruritus	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Eyelids pruritus	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Lacrimation increased	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Ocular hyperaemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Vision blurred	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Visual impairment	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal discomfort	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain upper	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Anorectal disorder	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Aptyalism	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Cheilitis	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	10.1% 7/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	84.1% 58/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dry mouth	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dyspepsia	10.1% 7/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dysphagia	11.6% 8/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Eructation	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Flatulence	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gingival pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Glossodynia	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Lip dry	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Lip haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Lip pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Mouth haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Mouth ulceration	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	21.7% 15/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Odynophagia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Oral pain	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Proctalgia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Proctitis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Rectal haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Saliva altered	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Salivary hypersecretion	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Stomatitis	33.3% 23/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Vomiting	14.5% 10/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Adverse drug reaction	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Chest pain	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Chills	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Face oedema	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Fatigue	50.7% 35/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Influenza like illness	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Irritability	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Local swelling	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Mucosal inflammation	15.9% 11/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Performance status decreased	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Pyrexia	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Candidiasis	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Cystitis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Fungal infection	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Groin infection	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Localised infection	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Nasopharyngitis	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Oral candidiasis	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Otitis media	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Paronychia	17.4% 12/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Pneumonia	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Rhinitis	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Skin infection	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Tinea pedis	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Urinary tract infection	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Excoriation	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Eye penetration	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Fall	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Post procedural haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Procedural site reaction	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Radiation skin injury	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Alanine aminotransferase increased	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Aspartate aminotransferase increased	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Blood creatinine increased	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Haemoglobin decreased	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Weight decreased	17.4% 12/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Decreased appetite	26.1% 18/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Dehydration	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypercalcaemia	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperkalaemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypokalaemia	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypomagnesaemia	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyponatraemia	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypophosphataemia	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Bone pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Fistula	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Flank pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Hypercreatinaemia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Muscular weakness	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Myalgia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Neck pain	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Pain in jaw	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Infected neoplasm	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Keratoacanthoma	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Cognitive disorder	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dysgeusia	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Hypoaesthesia	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Motor dysfunction	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Paraesthesia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Peripheral sensory neuropathy	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Sinus headache	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Somnolence	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders VIIth nerve paralysis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Anxiety	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Confusional state	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Depressed mood	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Insomnia	10.1% 7/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Libido decreased	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Mood altered	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Proteinuria	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Aspiration	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	18.8% 13/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dysphonia	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.6% 8/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	14.5% 10/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Haemoptysis	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Hiccups	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Laryngeal oedema	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Lung infiltration	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Nasal congestion	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Nasal dryness	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Obstructive airways disorder	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pharyngeal inflammation	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pneumothorax	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Respiratory disorder	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Rhinalgia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Sinus congestion	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Acne	13.0% 9/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Alopecia	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Decubitus ulcer	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Dermatitis acneiform	75.4% 52/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Dry skin	49.3% 34/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Erythema	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Erythema multiforme	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Exfoliative rash	24.6% 17/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Granuloma skin	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Hair colour changes	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Hair growth abnormal	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Ingrowing nail	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Nail bed inflammation	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Nail disorder	8.7% 6/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Onychomadesis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Pain of skin	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	34.8% 24/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Photosensitivity reaction	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Pruritus	29.0% 20/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Rash	15.9% 11/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Rash erythematous	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Scab	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin chapped	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin disorder	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin exfoliation	5.8% 4/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin fissures	7.2% 5/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Skin lesion	2.9% 2/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Telangiectasia	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Flushing	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypertension	4.3% 3/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypotension	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Intra-abdominal haematoma	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Lymphoedema	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Thrombosis	1.4% 1/69 The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Additional Information

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Results disclosure agreements

• Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
• Publication restrictions are in place

Restriction type: OTHER