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Clinical Trial Results:
Phase 1/2, Open-Label, Randomized Study of the Safety, Efficacy, and Pharmacokinetics of Letrozole Plus PD 0332991 (Oral CDK 4/6 Inhibitor) and Letrozole Single Agent for the First-Line Treatment of ER Positive, HER2 Negative Advanced Breast Cancer in Postmenopausal Women

Summary
EudraCT number	2008-002392-27
Trial protocol	IE HU DE FR IT ES GB
Global end of trial date	20 Dec 2017

Results information
Results version number	v1(current)
This version publication date	01 Dec 2018
First version publication date	01 Dec 2018
Other versions

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

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Trial information

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Sponsor protocol code

A5481003

ISRCTN number

US NCT number

NCT00721409

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

05 Jul 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

20 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

For Phase 1: To assess the safety and tolerability of palbociclib in combination with letrozole in postmenopausal women with Estrogen Receptor (ER)-positive, Human Epidermal Growth Factor Receptor 2 (HER2)-negative advanced breast cancer. For Phase 2: To assess the effect of palbociclib plus letrozole and of letrozole alone on progression-free survival (PFS) in the first-line treatment of ER-positive, HER2-negative advanced breast cancer in postmenopausal women.

Protection of trial subjects

The study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Sep 2008

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

86 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 43

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 25

Country: Number of subjects enrolled

Hungary: 26

Country: Number of subjects enrolled

Ireland: 18

Country: Number of subjects enrolled

Italy: 3

Country: Number of subjects enrolled

Russian Federation: 10

Country: Number of subjects enrolled

South Africa: 1

Country: Number of subjects enrolled

Korea, Republic of: 5

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

Ukraine: 24

Worldwide total number of subjects

177

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This Phase 1/2, open-label, randomized study enrolled a total of 12 subjects at 3 sites in the United States for Phase 1. Phase 1 subjects received Palbociclib + Letrozole. In Phase 2, a total of 165 subjects were randomized (84 in Palbociclib plus Letrozole arm and 81 in Letrozole alone arm) at 50 sites in 12 countries.

Screening details

Phase 2 portion has 2 parts. Phase 2, Part 1 – ER positive, HER2 negative postmenopausal women with advanced breast cancer. Phase 2, Part 2- ER positive, HER2 negative postmenopausal women with tumors demonstrating CCND1 gene amplification and/or loss of CDKN2A gene.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 (Palbociclib + Letrozole)

Arm description

In Cycle 1 (3 weeks), subjects received single agent Palbociclib 125 milligrams per day (mg/d) orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), subjects received Letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.

Arm type

Experimental

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD 0332991

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Palbociclib 125 milligram (mg) was administered orally, once in a day, up to 2 weeks followed by 1 week off treatment in Cycle 1. In Cycle 2 and beyond, Palbociclib 125 mg was administered orally once in a day for 3 weeks followed by 1 week off treatment. Cycle 1 was of 3 weeks and beyond that each cycle was of 4 weeks.

Investigational medicinal product name

Letrozole

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Letrozole 2.5 mg was administered orally, once in a day, up to 3 weeks followed by 1 week off treatment from Cycle 2 and beyond.

Phase 2 (Palbociclib + Letrozole)

Arm description

All subjects who were randomized to Letrozole plus Palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the subjects received Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.

Arm type

Experimental

Investigational medicinal product name

Letrozole

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Letrozole 2.5 mg was administered orally, once in a day, up to 3 weeks followed by 1 week off treatment from Cycle 2 and beyond.

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD 0332991

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Palbociclib 125 mg was administered orally, once in a day, up to 2 weeks followed by 1 week off treatment in Cycle 1. In Cycle 2 and beyond, Palbociclib 125 mg was administered orally once in a day for 3 weeks followed by 1 week off treatment. Cycle 1 was of 3 weeks and beyond that each cycle was of 4 weeks.

Phase 2 (Letrozole)

Arm description

All subjects who were randomized to receive Letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.

Arm type

Experimental

Investigational medicinal product name

Letrozole

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Letrozole 2.5 mg was administered orally, once in a day, up to 3 weeks followed by 1 week off treatment from Cycle 2 and beyond.

Number of subjects in period 1	Phase 1 (Palbociclib + Letrozole)	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)
Started	12	84	81
Treated	12	83	77
Completed	0	2	2
Not completed	12	82	79
Adverse event, serious fatal	-	1	-
Consent withdrawn by subject	1	6	5
Global deterioration of health status	2	6	3
Adverse event, non-fatal	-	13	2
Reason not specified	1	-	2
Objective progression or relapse	8	55	62
Lost to follow-up	-	-	1
Randomized not Treated	-	1	4

Baseline characteristics

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Reporting group title

Phase 1 (Palbociclib + Letrozole)

Reporting group description

Reporting group title

Phase 2 (Palbociclib + Letrozole)

Reporting group description

Reporting group title

Phase 2 (Letrozole)

Reporting group description

Reporting group values	Phase 1 (Palbociclib + Letrozole)	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Total
Number of subjects	12	84	81	177
Age, Customized
Units: Subjects
<18 Years	0	0	0	0
18-44 Years	1	2	4	7
45-64 Years	6	45	38	89
>= 65 Years	5	37	39	81
Age continuous
Units: years
arithmetic mean (standard deviation)	61.7 ( 9.65 )	62.7 ( 10.19 )	63.0 ( 9.16 )	-
Sex: Female, Male
Units: Subjects
Female	12	84	81	177
Male	0	0	0	0
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0
Asian	0	6	4	10
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	1	1	2
White	11	76	72	159
More than one race	0	0	0	0
Unknown or Not Reported	1	1	4	6

End points

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Reporting group title

Phase 1 (Palbociclib + Letrozole)

Reporting group description

Reporting group title

Phase 2 (Palbociclib + Letrozole)

Reporting group description

Reporting group title

Phase 2 (Letrozole)

Reporting group description

Subject analysis set title

Ph2P1 (Palbociclib + Letrozole)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.

Subject analysis set title

Ph2P1 (Letrozole)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects were randomized to receive Letrozole alone in Phase 2 Part 1. Letrozole 2.5 mg/d was administered orally in a continuous regimen.

Subject analysis set title

Ph2P2 (Palbociclib + Letrozole)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects were randomized to receive Letrozole plus Palbociclib in Phase 2 Part 2. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.

Subject analysis set title

Ph2P2 (Letrozole)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects were randomized to receive Letrozole alone in Phase 2 Part 2. Letrozole 2.5 mg/d was administered orally in a continuous regimen.

Subject analysis set title

Palbociclib alone (Cycle 1 Day 14)

Subject analysis set type

Sub-group analysis

Subject analysis set description

In Cycle 1 (3 weeks), subjects received single agent Palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment.

Subject analysis set title

Palbociclib + Letrozole (Cycle 2 Day 14)

Subject analysis set type

Sub-group analysis

Subject analysis set description

In Cycles 2 and beyond (4 weeks each), subjects received Letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.

Subject analysis set title

Letrozole alone (Cycle 2 Day 28)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received daily 2.5 mg doses of Letrozole alone.

Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 ^[1] ^[2]

End point description

AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. AEs included both serious and non-serious AEs. SAE: AE resulting in any of following outcomes/deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AE: events occurred between first dose of study drug and up to 28 days after last dose (up to 55 months) that were absent before treatment or worsened relative to pre-treatment state. AEs graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Subjects with AE of grade 3, 4 and grade 5 reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE. Safety analysis set: subjects who received at least 1 dose of study drug.

End point type

Primary

End point timeframe

Baseline up to 28 days after last dose of study drug (for a maximum of 55 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided’
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 1 (Palbociclib + Letrozole)
Number of subjects analysed	12
Units: subjects
Subjects with AEs	12
Subjects with SAEs	2
Subjects with Grade 3 or 4 AEs	11
Subjects with Grade 5 AEs	0

No statistical analyses for this end point

Primary: Number of Subjects With Treatment-Related Adverse Events at Phase 1

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End point title

Number of Subjects With Treatment-Related Adverse Events at Phase 1 ^[3] ^[4]

End point description

AE: any untoward medical occurrence in subject who received study drug. AEs included both serious and non-serious AEs. SAE: AE resulting in any of following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AEs: events occurred between first dose of study drug and up to 28 days after last dose (up to 55 months) that were absent before treatment or that worsened relative to pre-treatment state. Treatment related AEs: AEs with causality related to treatment. Relatedness to drug was assessed by the investigator. AEs graded according to the CTCAE version 3.0. Number of subjects with AE of grade 3, 4 and 5 were reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE. Safety analysis set: subjects who received at least 1 dose of study drug.

End point type

Primary

End point timeframe

Baseline up to 28 days after last dose of study drug (for a maximum of 55 months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided’
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 1 (Palbociclib + Letrozole)
Number of subjects analysed	12
Units: subjects
Subjects with AEs	12
Subjects with SAEs	0
Subjects with Grade 3 or 4 AEs	11
Subjects with Grade 5 AEs	0

No statistical analyses for this end point

Primary: Number of Subjects with Dose Limiting Toxicities (DLT) at Phase 1

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End point title

Number of Subjects with Dose Limiting Toxicities (DLT) at Phase 1 ^[5] ^[6]

End point description

DLT: any of following TEAEs occurred during second cycle of treatment and possibly attributable to combination of Letrozole+Palbociclib- 1:Grade 4 hematologic toxicity (including platelets less than [<] 25,000 per microliter [/mcL], absolute neutrophil count [ANC] <500/mcL). 2:Grade 3 neutropenia associated with a documented infection or fever greater than and equal to (>=) 38.5 degree Celsius (°C). 3:Grade >=3 non-hematologic toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea, hypertension). 4:Delay by >=1 week in receiving next scheduled dose of either study treatment due to persisting treatment-related toxicities (platelet count <50,000/mcL; ANC <1,000/mcL; nonhematologic toxicities of Grade >=3 severity). 5:Inability to deliver at least 80 percent (%) of planned Palbociclib or Letrozole doses during Cycle 2 due to toxicity possibly attributable to study treatment. Safety analysis set: subjects who received at least 1 dose of study drug.

End point type

Primary

End point timeframe

Cycle 2 (4 weeks)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint is descriptive in nature, no statistical analysis is provided’
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 1 (Palbociclib + Letrozole)
Number of subjects analysed	12
Units: subjects
Grade 4 Neutropenia	2
<80% of doses due to elevated creatinine	1

No statistical analyses for this end point

Primary: Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment

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End point title

Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment ^[7]

End point description

PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (weeks or months) = (first event date minus randomization or the first dose date plus 1) divided by 7 (or 30.44 if in months). PFS is usually characterized by the median, 25% percentile, 75% percentile and their 95% confidence intervals (CIs). Intent-to-Treat (ITT) population included randomized subjects from Phase 2, where subjects were classified according to the randomized treatment regardless of what treatment, if any, was received. Here, “99999” represents data was not available as upper limit of confidence interval was not reached.

End point type

Primary

End point timeframe

From randomization date to date of first documentation of progression or death (assessed up to 41 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	84	81	34	32	50	49
Units: Months
median (confidence interval 95%)	20.2 (13.8 to 27.5)	10.2 (5.7 to 12.6)	26.1 (11.2 to 99999)	5.7 (2.6 to 10.5)	18.1 (13.1 to 27.5)	11.1 (7.1 to 16.4)

Phase2(Palbociclib+Letrozole)vs.Phase2(Letrozole)

Statistical analysis description

The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the Palbociclib plus Letrozole: Letrozole alone HR. HR < 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Stratified analysis was presented above.

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0004 ^[8]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.488

Confidence interval

level

95%

sides

2-sided

lower limit

0.319

upper limit

0.748

Notes
[8] - 1-sided p-value from the log-rank test stratified by stratification factors per randomization and Part.

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the Palbociclib plus Letrozole: Letrozole alone HR. A HR < 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Unstratified analysis was presented above.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[9]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.299

Confidence interval

level

95%

sides

2-sided

lower limit

0.156

upper limit

0.572

Notes
[9] - 1-sided p-value from the log-rank test.

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0046 ^[10]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.508

Confidence interval

level

95%

sides

2-sided

lower limit

0.303

upper limit

0.853

Notes
[10] - 1-sided p-value from the log-rank test.

Secondary: Objective Response Rate - Percentage of Subjects with Confirmed Objective Tumor Response at Phase 1

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End point title

Objective Response Rate - Percentage of Subjects with Confirmed Objective Tumor Response at Phase 1 ^[11]

End point description

Percentage of subjects with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as >=30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. Efficacy analysis set included all enrolled subjects with disease under study, adequate baseline disease assessment, and who started study treatment.

End point type

Secondary

End point timeframe

From Baseline up to 55 months

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 1 (Palbociclib + Letrozole)
Number of subjects analysed	12
Units: percentage of subjects
number (confidence interval 95%)	33.3 (9.9 to 65.1)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Clinical Benefit Response (CBR) at Phase 1

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End point title

Percentage of Subjects With Clinical Benefit Response (CBR) at Phase 1 ^[12]

End point description

CBR was defined as a confirmed CR, confirmed PR, or stable disease (SD) for at least 24 weeks on study according to RECIST. Confirmed responses are those that persisted on repeat imaging >= 4 weeks after initial response. Efficacy analysis set included all enrolled subjects with disease under study, adequate baseline disease assessment, and who started study treatment.

End point type

Secondary

End point timeframe

From Baseline up to 55 months

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 1 (Palbociclib + Letrozole)
Number of subjects analysed	12
Units: percentage of subjects
number (confidence interval 95%)	83.3 (51.6 to 97.9)

No statistical analyses for this end point

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC24) at Phase 1

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End point title

Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC24) at Phase 1

End point description

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and Letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and Letrozole dosing. The pharmacokinetic parameter analysis set consisted of all subjects treated who had at least 1 of the pharmacokinetic parameters of primary interest.

End point type

Secondary

End point timeframe

Cycle 1 Day 14, and Cycle 2 Day 14

End point values	Palbociclib alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Number of subjects analysed	12	12
Units: nanogramhour per milliliter (nghr/mL)
geometric mean (geometric coefficient of variation)	1982 ( 29 )	1933 ( 31 )

No statistical analyses for this end point

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1

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End point title

Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1

End point description

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. The pharmacokinetic parameter analysis set consisted of all subjects treated who had at least 1 of the pharmacokinetic parameters of primary interest.

End point type

Secondary

End point timeframe

Cycle 1 Day 14, and Cycle 2 Day 14

End point values	Palbociclib alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Number of subjects analysed	12	12
Units: nanogram per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)	115.8 ( 28 )	108.4 ( 29 )

No statistical analyses for this end point

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1

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End point title

Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 14, and Cycle 2 Day 14

End point values	Palbociclib alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Number of subjects analysed	12	12
Units: Hour
median (full range (min-max))	7.92 (2.17 to 8.20)	7.92 (2.00 to 8.08)

No statistical analyses for this end point

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-Life (t1/2) at Phase 1

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End point title

Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-Life (t1/2) at Phase 1

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 14, and Cycle 2 Day 14

End point values	Palbociclib alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Number of subjects analysed	12	12
Units: Hour
arithmetic mean (standard deviation)	28.81 ( 5.0462 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1

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End point title

Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 14, and Cycle 2 Day 14

End point values	Palbociclib alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Number of subjects analysed	12	12
Units: Liter per hour (L/hr)
geometric mean (geometric coefficient of variation)	63.08 ( 29 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1

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End point title

Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 14, and Cycle 2 Day 14

End point values	Palbociclib alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Number of subjects analysed	12	12
Units: Liter
geometric mean (geometric coefficient of variation)	2583 ( 26 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1

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End point title

Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1

End point description

On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing. On Cycle 2 Day 28, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, and 24 hours after letrozole dosing. The pharmacokinetic parameter analysis set consisted of all subjects treated who had at least 1 of the pharmacokinetic parameters of primary interest.

End point type

Secondary

End point timeframe

Cycle 2 Day 14, Cycle 2 Day 28

End point values	Palbociclib + Letrozole (Cycle 2 Day 14)	Letrozole alone (Cycle 2 Day 28)
Number of subjects analysed	12	12
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	1739 ( 30 )	1936 ( 35 )

No statistical analyses for this end point

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1

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End point title

Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1

End point description

End point type

Secondary

End point timeframe

Cycle 2 Day 14, and Cycle 2 Day 28

End point values	Palbociclib + Letrozole (Cycle 2 Day 14)	Letrozole alone (Cycle 2 Day 28)
Number of subjects analysed	12	12
Units: ng/mL
geometric mean (geometric coefficient of variation)	94.95 ( 27 )	104.0 ( 31 )

No statistical analyses for this end point

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1

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End point title

Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1

End point description

End point type

Secondary

End point timeframe

Cycle 2 Day 14, and Cycle 2 Day 28

End point values	Palbociclib + Letrozole (Cycle 2 Day 14)	Letrozole alone (Cycle 2 Day 28)
Number of subjects analysed	12	12
Units: Hour
median (full range (min-max))	2.00 (0.833 to 4.13)	1.04 (0.00 to 4.42)

No statistical analyses for this end point

Secondary: Number of Subjects With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1

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End point title

Number of Subjects With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1 ^[13]

End point description

Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia’s formula (QTcF = QT divided by cube root of RR), by Bazette’s formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Subjects with maximum increase from baseline of 30 to < 60 msec(borderline) and >=60 msec (prolonged) were summarized. Safety analysis set: subjects who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 prior to dosing, Cycle 1 Day 14 (2, 4 [prior to meal], 8, 24, 48, and 96 hours after dosing of Palbociclib), Cycle 2 Day 1 and Day 14 (prior to and 4 hours after dosing of letrozole)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 1 (Palbociclib + Letrozole)
Number of subjects analysed	12
Units: subjects
QTcB - Change <30	9
QTcB - 30 <= change <60	3
QTcB - Change >=60	0
QTcF - Change <30	11
QTcF - 30 <= change <60	1
QTcF - Change >=60	0
QTcS - Change <30	8
QTcS - 30 <= change <60	4
QTcS - Change >=60	0

No statistical analyses for this end point

Secondary: Overall survival (OS) at Phase 2

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End point title

Overall survival (OS) at Phase 2 ^[14]

End point description

Time in weeks or months from randomization to date of death due to any cause. OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7 or 30.44 if in months. ITT population included randomized subjects from Phase 2, where subjects were classified according to the randomized treatment regardless of what treatment, if any, was received.

End point type

Secondary

End point timeframe

From randomization until death (assessed up to 86 months)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	84	81	34	32	50	49
Units: Months
median (confidence interval 95%)	37.5 (31.4 to 47.8)	34.5 (27.4 to 42.6)	37.5 (27.6 to 58.8)	33.3 (26.0 to 54.3)	35.1 (28.1 to 47.8)	35.7 (26.6 to 46.7)

Phase2(Palbociclib+Letrozole)vsPhase2(Letrozole)

Statistical analysis description

Stratified analysis was presented above. HR was assuming proportional hazards, HR < 1 indicated a reduction in hazard rate in favor of Palbociclib + Letrozole.

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2812 ^[15]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.897

Confidence interval

level

95%

sides

2-sided

lower limit

0.623

upper limit

1.294

Notes
[15] - 1-sided p-value from the log-rank test stratified by Part (α = 0.10).

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

Unstratified analysis was presented above.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2803 ^[16]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.837

Confidence interval

level

95%

sides

2-sided

lower limit

0.458

upper limit

1.527

Notes
[16] - 1-sided p-value from the unstratified log-rank test (α=0.10).

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Unstratified analysis was presented above.

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3875 ^[17]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.935

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

1.48

Notes
[17] - 1-sided p-value from the unstratified log-rank test (α=0.10).

Secondary: Objective Response Rate - Percentage of Subjects With Confirmed Objective Response at Phase 2- Investigator Assessment

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End point title

Objective Response Rate - Percentage of Subjects With Confirmed Objective Response at Phase 2- Investigator Assessment ^[18]

End point description

Percentage of subjects with objective response based assessment of confirmed CR or PR according to RECIST. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0, CR defined as disappearance of all target lesions and non-target lesions. PR defined as >=30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressive disease response for non target lesions. ITT population included randomized subjects from Phase 2, where subjects were classified according to the randomized treatment regardless of what treatment, if any, was received.

End point type

Secondary

End point timeframe

From randomization up to 41 months

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

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	84	81	34	32	50	49
Units: Percentage of subjects
number (confidence interval 95%)	42.9 (32.1 to 54.1)	33.3 (23.2 to 44.7)	44.1 (27.2 to 62.1)	25.0 (11.5 to 43.4)	42.0 (28.2 to 56.8)	38.8 (25.2 to 53.8)

Phase2(Palbociclib+Letrozole)vsPhase2(Letrozole)

Statistical analysis description

Objective Response CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio >1 means better response in favor of Palbociclib + Letrozole arm.

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1347 ^[19]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

2.97

Notes
[19] - 1-sided p-value is from the stratified exact test (1-sided, α =0.10)

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0849 ^[20]

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

2.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

7.84

Notes
[20] - Chi-square test was used (1-sided, α=0.10)

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4515 ^[21]

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

2.76

Notes
[21] - Chi-square test was used (1-sided, α=0.10)

Secondary: Objective Response Rate - Percentage of Subjects with Confirmed Objective Response in Subjects With Measurable Disease at Phase 2- Investigator Assessment

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End point title

Objective Response Rate - Percentage of Subjects with Confirmed Objective Response in Subjects With Measurable Disease at Phase 2- Investigator Assessment ^[22]

End point description

Percentage of subjects with objective response based on assessment of confirmed CR or PR as per RECIST. CR: those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR: disappearance of all target and non-target lesions. PR: >=30% decrease in sum of LD of target lesions reference to baseline sum LD as per RECIST associated to non-progressive disease response for non target lesions. Measurable disease: lesions accurately measured in at least 1 dimension (longest diameter to be recorded) as >=20 mm with conventional techniques or as >=10-16 mm with spiral computer tomography scan. Clinical lesions considered measurable when they were superficial (eg, skin nodules, palpable lymph nodes). ITT population: randomized subjects from Phase 2, classified according to randomized treatment regardless of what treatment, if any, was received. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm.

End point type

Secondary

End point timeframe

From randomization up to 41 months

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

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	65	66	27	23	21	43
Units: Percentage of subjects
number (confidence interval 95%)	55.4 (42.5 to 67.7)	39.4 (27.6 to 52.2)	55.6 (35.3 to 74.5)	34.8 (16.4 to 57.3)	55.3 (38.3 to 71.4)	41.9 (27.0 to 57.9)

Phase2(Palbociclib+Letrozole)vsPhase2(Letrozole)

Statistical analysis description

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

131

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0471 ^[23]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

1.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

4.08

Notes
[23] - 1-sided p-value is from the stratified exact test (1-sided, α =0.10)

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.118 ^[24]

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

2.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

8.66

Notes
[24] - Chi-square test was used (1-sided, α=0.10)

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1631 ^[25]

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

1.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

4.54

Notes
[25] - Chi-square test was used (1-sided, α=0.10)

Secondary: Duration of Response at Phase 2 - Investigator Assessment

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End point title

Duration of Response at Phase 2 - Investigator Assessment ^[26]

End point description

Time in months from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. Time to progression was calculated as (first event date or last known progression-free date minus the date of randomization [or first dose of study medication for non-randomized studies] plus 1) divided by 30.44. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per RECIST). ITT population included randomized subjects from Phase 2, where subjects were classified according to the randomized treatment regardless of what treatment, if any, was received. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm and “99999” represents data not available as upper limit of confidence interval was not reached.

End point type

Secondary

End point timeframe

From randomization up to 41 months

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

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	36	27	15	8	21	19
Units: Months
median (confidence interval 95%)	20.3 (13.4 to 25.8)	11.1 (9.3 to 31.6)	20.9 (6.2 to 25.8)	10.8 (3.7 to 31.6)	20.2 (13.0 to 99999)	14.8 (7.4 to 99999)

No statistical analyses for this end point

Secondary: Number of Subjects With CBR at Phase 2 - Investigator Assessment

Top of page

End point title

Number of Subjects With CBR at Phase 2 - Investigator Assessment ^[27]

End point description

CBR was defined as a confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) for at least 24 weeks on study according to RECIST. ITT population included randomized subjects from Phase 2, where subjects were classified according to the randomized treatment regardless of what treatment, if any, was received.

End point type

Secondary

End point timeframe

From randomization up to 41 months

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

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	84	81	34	32	50	49
Units: Percentage of subjects
number (confidence interval 95%)	81.0 (70.9 to 88.7)	58.0 (46.5 to 68.9)	76.5 (58.8 to 89.3)	43.8 (26.4 to 62.3)	84.0 (70.9 to 92.8)	67.3 (52.5 to 80.1)

Phase2(Palbociclib+Letrozole)vsPhase2(Letrozole)

Statistical analysis description

CBR CI was calculated using the exact Clopper-Pearson method. The stratified analysis presented above was based on CMH test stratified by Part. An Odds Ratio >1 means better response in favor of palbociclib + letrozole arm.

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0009 ^[28]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

3.18

Confidence interval

level

95%

sides

2-sided

lower limit

1.48

upper limit

6.98

Notes
[28] - 1-sided p-value is from the stratified exact test (1-sided, α =0.10).

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0065 ^[29]

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

4.18

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

13.9

Notes
[29] - Chi-square test was used (1-sided, α=0.10)

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0442 ^[30]

Method

Chi-squared

Parameter type

Odds ratio (OR)

Point estimate

2.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

7.7

Notes
[30] - Chi-square test was used (1-sided, α=0.10)

Secondary: Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment

Top of page

End point title

Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment ^[31]

End point description

Time in months from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. Time to progression was calculated as (first event date or last known progression-free date minus the date of randomization [or first dose of study medication for non-randomized studies] plus 1) divided by 30.44. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per RECIST). ITT population included randomized subjects from Phase 2, where subjects were classified according to the randomized treatment regardless of what treatment, if any, was received. Here, “99999” represents data not available as upper limit of confidence interval was not reached.

End point type

Secondary

End point timeframe

From randomization up to 41 months

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	84	81	34	32	50	49
Units: Months
median (confidence interval 95%)	20.2 (13.8 to 27.5)	10.2 (5.7 to 12.6)	26.1 (11.2 to 99999)	5.7 (2.6 to 10.5)	18.8 (13.1 to 27.5)	11.1 (7.1 to 16.4)

Phase2(Palbociclib+Letrozole)vsPhase2(Letrozole)

Statistical analysis description

Kaplan-Meier method was applied for median and 95% CI. HR was based on assuming proportional hazards, HR < 1 indicates a reduction in hazard rate in favor of palbociclib + letrozole.

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

165

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[32]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.399

Confidence interval

level

95%

sides

2-sided

lower limit

0.265

upper limit

0.601

Notes
[32] - 1-sided p-value is from the stratified log-rank test (α =0.10).

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[33]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.299

Confidence interval

level

95%

sides

2-sided

lower limit

0.156

upper limit

0.572

Notes
[33] - 1-sided p-value is from unstratified log-rank test (α=0.10).

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.003 ^[34]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.486

Confidence interval

level

95%

sides

2-sided

lower limit

0.288

upper limit

0.822

Notes
[34] - 1-sided p-value is from unstratified log-rank test (α=0.10).

Secondary: Change from Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2

Top of page

End point title

Change from Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2 ^[35]

End point description

The mBPI-sf is a validated and reliable self-report questionnaire which consists of 13 questions that assess the severity and impact of pain on daily function. The 13 items of the questionnaire make up two scales and two single items. The scales include the 4-item Pain Severity Scale (worst pain, least pain, average pain, and pain right now) and the 7-item Pain Interference Scale (general activity, mood, walking ability, normal work and relations with other people, sleep, and enjoyment of life). Each item of the pain severity and pain interference scales are based on a 11-point numeric rating scale from 0 (“no pain” or “does not interfere”) to 10 (“pain as bad as you can imagine” or “completely interferes”). Patient reported outcome evaluable subjects: who had received at least 1 dose of study medication, had baseline data, and at least one post-baseline measurement. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm.

End point type

Secondary

End point timeframe

Baseline, Month 41

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	76	74	29	27	47	47
Units: Units on a scale
arithmetic mean (standard error)
Pain at its worst in the last 24 hours	0.6 ( 0.42 )	0.1 ( 0.42 )	0.2 ( 0.60 )	0.0 ( 0.89 )	1.2 ( 0.55 )	0.1 ( 0.43 )
Pain at its least in the last 24 hours	0.4 ( 0.27 )	0.4 ( 0.27 )	0.3 ( 0.31 )	0.7 ( 0.50 )	0.5 ( 0.40 )	0.2 ( 0.31 )
Pain on the average	0.2 ( 0.33 )	0.2 ( 0.34 )	-0.1 ( 0.48 )	0.2 ( 0.64 )	0.4 ( 0.45 )	0.3 ( 0.40 )
Pain right now	0.3 ( 0.35 )	0.1 ( 0.36 )	0.1 ( 0.31 )	0.3 ( 0.66 )	0.3 ( 0.55 )	0.0 ( 0.43 )
Pain Severity Scale	0.4 ( 0.29 )	0.2 ( 0.32 )	0.0 ( 0.36 )	0.3 ( 0.62 )	0.6 ( 0.41 )	0.1 ( 0.36 )

Phase2(Palbociclib+Letrozole)vsPhase2(Letrozole)

Statistical analysis description

Statistical analysis presented above is for Pain Severity Scale.

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

P-value

= 0.69 ^[36]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

Notes
[36] - P-values are based on 2-sample t-test.

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

Statistical analysis presented above is for Pain Severity Scale.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7125 ^[37]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

1.2

Notes
[37] - P-values are based on 2-sample t-test.

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Statistical analysis presented above is for Pain Severity Scale.

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4012 ^[38]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

1.5

Notes
[38] - P-values are based on 2-sample t-test.

Secondary: Change from Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2

Top of page

End point title

Change from Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2 ^[39]

End point description

End point type

Secondary

End point timeframe

Baseline, Month 41

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	76	74	29	27	47	47
Units: Units on a scale
arithmetic mean (standard error)
General Activity	1.1 ( 0.40 )	0.2 ( 0.31 )	1.0 ( 0.66 )	0.2 ( 0.58 )	1.2 ( 0.51 )	0.3 ( 0.37 )
Mood	0.8 ( 0.50 )	0.2 ( 0.36 )	0.6 ( 0.72 )	-0.2 ( 0.62 )	1.0 ( 0.69 )	0.4 ( 0.44 )
Walking ability	0.8 ( 0.46 )	0.1 ( 0.35 )	1.0 ( 0.55 )	0.3 ( 0.63 )	0.7 ( 0.67 )	0.0 ( 0.43 )
Normal work	0.7 ( 0.48 )	0.3 ( 0.39 )	1.0 ( 0.53 )	0.2 ( 0.74 )	0.5 ( 0.71 )	0.4 ( 0.45 )
Relations	0.8 ( 0.32 )	0.8 ( 0.32 )	0.6 ( 0.34 )	0.6 ( 0.60 )	0.9 ( 0.47 )	0.8 ( 0.37 )
Sleep	0.6 ( 0.43 )	0.3 ( 0.35 )	0.1 ( 0.53 )	0.5 ( 0.63 )	0.9 ( 0.61 )	0.1 ( 0.42 )
Enjoyment of life	0.8 ( 0.46 )	0.6 ( 0.41 )	0.4 ( 0.34 )	0.2 ( 0.69 )	1.1 ( 0.71 )	0.8 ( 0.52 )
Pain Interference Scale	0.8 ( 0.34 )	0.4 ( 0.30 )	0.7 ( 0.42 )	0.3 ( 0.56 )	0.9 ( 0.48 )	0.4 ( 0.36 )

Phase2(Palbociclib+Letrozole)vsPhase2(Letrozole)

Statistical analysis description

Statistical analysis presented above is for Pain Interference Scale.

Comparison groups

Phase 2 (Palbociclib + Letrozole) v Phase 2 (Letrozole)

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3346 ^[40]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

1.3

Notes
[40] - P-values are based on 2-sample t-test.

Ph2P1(Palbociclib+Letrozole)vsPh2P1(Letrozole)

Statistical analysis description

Statistical analysis presented above is for Pain Interference Scale.

Comparison groups

Ph2P1 (Palbociclib + Letrozole) v Ph2P1 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.563 ^[41]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

1.9

Notes
[41] - P-values are based on 2-sample t-test.

Ph2P2(Palbociclib+Letrozole)vsPh2P2(Letrozole)

Statistical analysis description

Statistical analysis presented above is for Pain Severity Scale.

Comparison groups

Ph2P2 (Palbociclib + Letrozole) v Ph2P2 (Letrozole)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4427 ^[42]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.6

Notes
[42] - P-values are based on 2-sample t-test.

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1

Top of page

End point title

Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1

End point description

Tissue samples were used for retrospective biomarker analyses. For Phase 2 Part 2, the tissue samples were sent to a central laboratory for the assessment of subject selection biomarkers. For Phase 2 Part 1, the assessment of the biomarkers (CCND1 amplification and/or loss of p16) were performed retrospectively from the available samples. Copy number analysis set included subjects who had at least 1 of the biomarker assessments. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm.

End point type

Secondary

End point timeframe

Screening visit (<= 28 days prior to dosing)

End point values	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	22	24	50	48
Units: Subjects
CCND1>=1.5	12	9	39	44
p16/INK4A<0.8	0	2	19	12
CCND1>=1.5 and p16/INK4A<0.8	0	2	8	8

No statistical analyses for this end point

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67

Top of page

End point title

Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67 ^[43]

End point description

Frequency of tumor tissue biomarker Ki67 was evaluated in across treatment groups. Ki67 analysis set included subjects who had a Ki67 protein biomarker assessment. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm.

End point type

Secondary

End point timeframe

Screening visit (<= 28 days prior to dosing)

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	74	71	24	26	50	45
Units: Subjects
<=20%	26	31	7	16	19	15
>20%	48	40	17	10	31	30

No statistical analyses for this end point

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1

Top of page

End point title

Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1 ^[44]

End point description

Presence or absence of tumor RB and CyclinD1 were evaluated. The following definitions of expression applied in the below table: Positive: any expression >0 and Negative: any expression=0. Protein biomarkers analysis set included all subjects who had at least protein biomarker assessment. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm.

End point type

Secondary

End point timeframe

Screening visit (<= 28 days prior to dosing)

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	45	35	12	16	33	19
Units: Subjects
CyclinD1 - Positive	41	32	10	16	31	16
CyclinD1 - Negative	3	3	2	0	1	3
RB - Positive	41	32	10	16	31	16
RB - Negative	2	2	2	0	0	2

No statistical analyses for this end point

Secondary: Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2

Top of page

End point title

Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2 ^[45]

End point description

Gene copy number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) were evaluated. This analysis was done for Phase 2 combined group. Copy number analysis set included all subjects who had at least one copy number assessment. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm.

End point type

Secondary

End point timeframe

Screening visit (<= 28 days prior to dosing)

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)
Number of subjects analysed	72	72
Units: Copy number
arithmetic mean (standard deviation)
CCND1	2.76 ( 1.875 )	2.73 ( 1.559 )
p16/INK4A	0.83 ( 0.224 )	0.87 ( 0.173 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2

Top of page

End point title

Percentage of Subjects With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2 ^[46]

End point description

One 2-mL blood specimen was collected for the analysis of germline polymorphism in CYP19A1 and CCND1 genes. A single nucleotide polymorphism (SNP) rs4646 as defined in the National Center for Biotechnology Information (NCBI) database in the aromatase gene (CYP19A1) was analyzed. A germline polymorphism G/A870 (rs9344) in the CCND1 gene was analyzed. Polymorphism analysis set included subjects who had at least 1 polymorphism assessment. Here, “number of subjects analyzed” signifies number of subjects evaluable for this endpoint for each arm.

End point type

Secondary

End point timeframe

Screening visit (<= 28 days prior to dosing)

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	76	74	30	28	46	46
Units: Percentage of subjects
number (not applicable)
CYP19A1 - A/A Genotype	7.9	5.4	10.0	10.7	6.5	2.2
CYP19A1 - C/A Genotype	34.2	36.5	33.3	42.9	34.8	32.6
CYP19A1 - C/C Genotype	57.9	58.1	56.7	46.4	58.7	65.2
CCND1 - A/A Genotype	26.3	28.4	33.3	39.3	21.7	21.7
CCND1 - G/A Genotype	47.4	47.3	43.3	42.9	50.0	50.0
CCND1 - G/G Genotype	26.3	24.3	23.3	17.9	28.3	28.3

No statistical analyses for this end point

Secondary: Number of Subjects with TEAEs (All Causalities) at Phase 2

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End point title

Number of Subjects with TEAEs (All Causalities) at Phase 2 ^[47]

End point description

AE: any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. AEs included both serious and non-serious AEs. SAE: AE resulting in any of following outcomes/deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AE: events occurred between first dose of study drug and up to 28 days after last dose (up to 86 months) that were absent before treatment or worsened relative to pre-treatment state. AEs graded as per the CTCAE version 3.0. Subjects with AE of grade 3, 4 and grade 5 reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE. All treated as treated set included all treated subjects classified by treatment actually received.

End point type

Secondary

End point timeframe

Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	83	77	33	29	50	48
Units: Subjects
Subjects with AEs	83	66	33	25	50	41
Subjects with SAEs	22	6	10	2	12	4
Subjects with Grade 3 or 4 AEs	70	19	29	5	41	14
Subjects with Grade 5 AEs	1	0	0	0	1	0

No statistical analyses for this end point

Secondary: Number of Subjects with Treatment-Related Adverse Events at Phase 2

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End point title

Number of Subjects with Treatment-Related Adverse Events at Phase 2 ^[48]

End point description

AE: any untoward medical occurrence in subject who received study drug. AEs included both serious and non-serious AEs. SAE: AE resulting in any of following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs: events occurred between first dose of study drug and up to 28 days after last dose (up to 86 months) that were absent before treatment or that worsened relative to pre-treatment state. Treatment related AEs: AEs with causality related to treatment. Relatedness to drug was assessed by the investigator. AEs graded according to the CTCAE version 3.0. Number of subjects with AE of grade 3, 4 and 5 were reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE. All treated as treated set included all treated subjects classified by treatment actually received.

End point type

Secondary

End point timeframe

Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only arms which are applicable to the endpoint are reported.

End point values	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Number of subjects analysed	83	77	33	29	50	48
Units: Subjects
Subjects with AEs	78	33	32	13	46	20
Subjects with SAEs	1	0	0	0	1	0
Subjects with Grade 3 or 4 AEs	57	2	25	0	32	2
Subjects with Grade 5 AEs	0	0	0	0	0	0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)

Adverse event reporting additional description

An event may be categorized as serious in one subject and non serious in another, or 1 subject may experience both event. All treatment emergent AEs and SAEs were collected and reported. The same event may appear as both AE and SAE. Analysis was done on subjects who received at least one dose of study drug.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Phase 1 (Palbociclib + Letrozole)

Reporting group description

In Cycle 1 (3 weeks), subjects received single agent palbociclib 125 mg/d orally for 2 weeks followed by 1 week off treatment. In Cycles 2 and beyond (4 weeks each), subjects received letrozole 2.5 mg/d in a continuous regimen plus Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment.

Reporting group title

Phase 2 (Palbociclib + Letrozole)

Reporting group description

All participants who were randomized to letrozole plus palbociclib in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. In Ph2P1 and Ph2P2, the participants received palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and letrozole 2.5 mg/d orally in a continuous regimen.

Reporting group title

Phase 2 (Letrozole)

Reporting group description

All participants who were randomized to receive letrozole alone in both Phase 2 part 1 (Ph2P1) and Phase 2 part 2 (Ph2P2) are combined and presented. This was considered as control arm. Letrozole 2.5 mg/d was administered orally in a continuous regimen.

Reporting group title

Ph2P1 (Palbociclib + Letrozole)

Reporting group description

All participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.

Reporting group title

Ph2P1 (Letrozole)

Reporting group description

Participants were randomized to receive Letrozole alone. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.

Reporting group title

Ph2P2 (Palbociclib + Letrozole)

Reporting group description

Participants were randomized to receive Letrozole plus Palbociclib. Palbociclib 125 mg/d orally for 3 weeks followed by 1 week off treatment and Letrozole 2.5 mg/d orally in a continuous regimen.

Reporting group title

Ph2P2 (Letrozole)

Reporting group description

Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.

Serious adverse events	Phase 1 (Palbociclib + Letrozole)	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 12 (16.67%)	22 / 83 (26.51%)	6 / 77 (7.79%)	10 / 33 (30.30%)	2 / 29 (6.90%)	12 / 50 (24.00%)	4 / 48 (8.33%)
number of deaths (all causes)	0	3	1	1	0	2	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Fallopian tube cancer
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pain
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fractured sacrum
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Neuralgia
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain stem infarction
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal achalasia
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Subcutaneous emphysema
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal disorder
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urethral obstruction
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	2 / 50 (4.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Erysipelas
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter infection
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase 1 (Palbociclib + Letrozole)	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Total subjects affected by non serious adverse events
subjects affected / exposed	12 / 12 (100.00%)	83 / 83 (100.00%)	57 / 77 (74.03%)	33 / 33 (100.00%)	22 / 29 (75.86%)	50 / 50 (100.00%)	35 / 48 (72.92%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	3	0	0	0	3	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	2	0	0	0
Hot flush
subjects affected / exposed	3 / 12 (25.00%)	19 / 83 (22.89%)	11 / 77 (14.29%)	9 / 33 (27.27%)	5 / 29 (17.24%)	10 / 50 (20.00%)	6 / 48 (12.50%)
occurrences all number	5	21	12	10	6	11	6
Hypertension
subjects affected / exposed	0 / 12 (0.00%)	6 / 83 (7.23%)	5 / 77 (6.49%)	1 / 33 (3.03%)	2 / 29 (6.90%)	5 / 50 (10.00%)	3 / 48 (6.25%)
occurrences all number	0	6	7	1	2	5	5
Lymphoedema
subjects affected / exposed	0 / 12 (0.00%)	4 / 83 (4.82%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	2 / 50 (4.00%)	0 / 48 (0.00%)
occurrences all number	0	4	0	2	0	2	0
Peripheral vascular disorder
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Phlebitis
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 12 (8.33%)	11 / 83 (13.25%)	4 / 77 (5.19%)	2 / 33 (6.06%)	0 / 29 (0.00%)	9 / 50 (18.00%)	4 / 48 (8.33%)
occurrences all number	1	14	4	2	0	12	4
Chest pain
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	4 / 77 (5.19%)	0 / 33 (0.00%)	2 / 29 (6.90%)	3 / 50 (6.00%)	2 / 48 (4.17%)
occurrences all number	0	4	4	0	2	4	2
Facial pain
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Fatigue
subjects affected / exposed	10 / 12 (83.33%)	34 / 83 (40.96%)	18 / 77 (23.38%)	14 / 33 (42.42%)	7 / 29 (24.14%)	20 / 50 (40.00%)	11 / 48 (22.92%)
occurrences all number	20	70	29	31	14	39	15
Influenza like illness
subjects affected / exposed	1 / 12 (8.33%)	5 / 83 (6.02%)	2 / 77 (2.60%)	3 / 33 (9.09%)	1 / 29 (3.45%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	1	7	2	5	1	2	1
Mucosal inflammation
subjects affected / exposed	0 / 12 (0.00%)	7 / 83 (8.43%)	2 / 77 (2.60%)	2 / 33 (6.06%)	0 / 29 (0.00%)	5 / 50 (10.00%)	2 / 48 (4.17%)
occurrences all number	0	12	2	5	0	7	2
Non-cardiac chest pain
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	2 / 12 (16.67%)	6 / 83 (7.23%)	8 / 77 (10.39%)	3 / 33 (9.09%)	5 / 29 (17.24%)	3 / 50 (6.00%)	3 / 48 (6.25%)
occurrences all number	2	8	11	5	6	3	5
Pain
subjects affected / exposed	2 / 12 (16.67%)	3 / 83 (3.61%)	3 / 77 (3.90%)	1 / 33 (3.03%)	2 / 29 (6.90%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	3	3	3	1	2	2	1
Pyrexia
subjects affected / exposed	0 / 12 (0.00%)	9 / 83 (10.84%)	2 / 77 (2.60%)	8 / 33 (24.24%)	0 / 29 (0.00%)	1 / 50 (2.00%)	2 / 48 (4.17%)
occurrences all number	0	10	2	9	0	1	2
Temperature intolerance
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Chills
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	1	0	0	0
Face oedema
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	1 / 77 (1.30%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 50 (2.00%)	1 / 48 (2.08%)
occurrences all number	1	2	1	1	0	1	1
Peripheral swelling
subjects affected / exposed	1 / 12 (8.33%)	4 / 83 (4.82%)	2 / 77 (2.60%)	2 / 33 (6.06%)	0 / 29 (0.00%)	2 / 50 (4.00%)	2 / 48 (4.17%)
occurrences all number	1	4	2	2	0	2	2
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 12 (16.67%)	1 / 83 (1.20%)	1 / 77 (1.30%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	3	2	1	2	1	0	0
Reproductive system and breast disorders
Breast discomfort
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	2	0	0	0
Breast pain
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	4 / 77 (5.19%)	2 / 33 (6.06%)	3 / 29 (10.34%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	3	4	3	3	0	1
Pelvic pain
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	2 / 77 (2.60%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 50 (2.00%)	2 / 48 (4.17%)
occurrences all number	1	2	3	1	0	1	3
Vaginal discharge
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	1	0	1	0	0
Vulvovaginal pruritus
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 12 (25.00%)	12 / 83 (14.46%)	8 / 77 (10.39%)	9 / 33 (27.27%)	4 / 29 (13.79%)	3 / 50 (6.00%)	4 / 48 (8.33%)
occurrences all number	6	21	13	18	4	3	9
Dyspnoea
subjects affected / exposed	5 / 12 (41.67%)	14 / 83 (16.87%)	7 / 77 (9.09%)	4 / 33 (12.12%)	3 / 29 (10.34%)	10 / 50 (20.00%)	4 / 48 (8.33%)
occurrences all number	7	20	8	9	3	11	5
Epistaxis
subjects affected / exposed	0 / 12 (0.00%)	9 / 83 (10.84%)	1 / 77 (1.30%)	4 / 33 (12.12%)	0 / 29 (0.00%)	5 / 50 (10.00%)	1 / 48 (2.08%)
occurrences all number	0	12	1	6	0	6	1
Nasal congestion
subjects affected / exposed	2 / 12 (16.67%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	2	3	0	3	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 12 (8.33%)	9 / 83 (10.84%)	1 / 77 (1.30%)	5 / 33 (15.15%)	0 / 29 (0.00%)	4 / 50 (8.00%)	1 / 48 (2.08%)
occurrences all number	1	15	1	10	0	5	1
Rhinitis allergic
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	1	0	1	1	0
Rhinorrhoea
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	0	0	1	0
Sinus congestion
subjects affected / exposed	3 / 12 (25.00%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	3	1	0	1	0	0	0
Snoring
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Lower respiratory tract congestion
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	4 / 77 (5.19%)	2 / 33 (6.06%)	4 / 29 (13.79%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	2	2	5	2	5	0	0
Depression
subjects affected / exposed	3 / 12 (25.00%)	4 / 83 (4.82%)	5 / 77 (6.49%)	2 / 33 (6.06%)	4 / 29 (13.79%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	3	4	5	2	4	2	1
Insomnia
subjects affected / exposed	3 / 12 (25.00%)	8 / 83 (9.64%)	6 / 77 (7.79%)	4 / 33 (12.12%)	3 / 29 (10.34%)	4 / 50 (8.00%)	3 / 48 (6.25%)
occurrences all number	3	9	7	4	3	5	4
Mood altered
subjects affected / exposed	1 / 12 (8.33%)	4 / 83 (4.82%)	1 / 77 (1.30%)	2 / 33 (6.06%)	0 / 29 (0.00%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	2	7	1	3	0	4	1
Sleep disorder
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	3 / 50 (6.00%)	1 / 48 (2.08%)
occurrences all number	0	3	1	0	0	3	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	6 / 83 (7.23%)	1 / 77 (1.30%)	3 / 33 (9.09%)	1 / 29 (3.45%)	3 / 50 (6.00%)	0 / 48 (0.00%)
occurrences all number	0	8	1	5	1	3	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 12 (0.00%)	6 / 83 (7.23%)	1 / 77 (1.30%)	2 / 33 (6.06%)	1 / 29 (3.45%)	4 / 50 (8.00%)	0 / 48 (0.00%)
occurrences all number	0	11	1	6	1	5	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 12 (0.00%)	8 / 83 (9.64%)	3 / 77 (3.90%)	2 / 33 (6.06%)	2 / 29 (6.90%)	6 / 50 (12.00%)	1 / 48 (2.08%)
occurrences all number	0	10	3	4	2	6	1
Blood creatinine increased
subjects affected / exposed	2 / 12 (16.67%)	4 / 83 (4.82%)	5 / 77 (6.49%)	1 / 33 (3.03%)	3 / 29 (10.34%)	3 / 50 (6.00%)	2 / 48 (4.17%)
occurrences all number	7	4	5	1	3	3	2
Blood phosphorus decreased
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	2	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 12 (0.00%)	4 / 83 (4.82%)	1 / 77 (1.30%)	2 / 33 (6.06%)	0 / 29 (0.00%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	0	14	1	12	0	2	1
Red blood cell count decreased
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	2	0	0	0
Weight decreased
subjects affected / exposed	2 / 12 (16.67%)	4 / 83 (4.82%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	4 / 50 (8.00%)	0 / 48 (0.00%)
occurrences all number	2	5	1	0	1	5	0
White blood cell count decreased
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	5	0	5	0	0	0
Weight increased
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	6 / 77 (7.79%)	1 / 33 (3.03%)	2 / 29 (6.90%)	2 / 50 (4.00%)	4 / 48 (8.33%)
occurrences all number	0	5	9	1	2	4	7
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 12 (16.67%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	2	1	0	1	0	0	0
Thermal burn
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	0	0	1	0
Fall
subjects affected / exposed	0 / 12 (0.00%)	7 / 83 (8.43%)	3 / 77 (3.90%)	4 / 33 (12.12%)	0 / 29 (0.00%)	3 / 50 (6.00%)	3 / 48 (6.25%)
occurrences all number	0	14	3	7	0	7	3
Periorbital haemorrhage
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	1	0	1	0	0
Skin abrasion
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	2	0	2	0	0	0
Skin injury
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	0	0	1	0
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 12 (25.00%)	10 / 83 (12.05%)	3 / 77 (3.90%)	3 / 33 (9.09%)	3 / 29 (10.34%)	7 / 50 (14.00%)	0 / 48 (0.00%)
occurrences all number	3	15	4	3	4	12	0
Dysgeusia
subjects affected / exposed	1 / 12 (8.33%)	6 / 83 (7.23%)	0 / 77 (0.00%)	4 / 33 (12.12%)	0 / 29 (0.00%)	2 / 50 (4.00%)	0 / 48 (0.00%)
occurrences all number	1	7	0	5	0	2	0
Headache
subjects affected / exposed	4 / 12 (33.33%)	12 / 83 (14.46%)	8 / 77 (10.39%)	6 / 33 (18.18%)	3 / 29 (10.34%)	6 / 50 (12.00%)	5 / 48 (10.42%)
occurrences all number	5	21	10	14	4	7	6
Memory impairment
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	1 / 77 (1.30%)	1 / 33 (3.03%)	1 / 29 (3.45%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	2	1	1	1	1	0
Neuropathy peripheral
subjects affected / exposed	2 / 12 (16.67%)	9 / 83 (10.84%)	4 / 77 (5.19%)	6 / 33 (18.18%)	2 / 29 (6.90%)	3 / 50 (6.00%)	2 / 48 (4.17%)
occurrences all number	3	11	4	8	2	3	2
Paraesthesia
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	2 / 77 (2.60%)	0 / 33 (0.00%)	2 / 29 (6.90%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	2	0	2	1	0
Sciatica
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	2	0	2	0	0	0
Sinus headache
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Syncope
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Radicular pain
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	3 / 50 (6.00%)	0 / 48 (0.00%)
occurrences all number	0	6	0	0	0	6	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 12 (33.33%)	29 / 83 (34.94%)	3 / 77 (3.90%)	13 / 33 (39.39%)	0 / 29 (0.00%)	16 / 50 (32.00%)	3 / 48 (6.25%)
occurrences all number	19	90	7	55	0	35	7
Leukopenia
subjects affected / exposed	8 / 12 (66.67%)	36 / 83 (43.37%)	3 / 77 (3.90%)	16 / 33 (48.48%)	1 / 29 (3.45%)	20 / 50 (40.00%)	2 / 48 (4.17%)
occurrences all number	70	172	4	127	1	45	3
Lymphopenia
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	0	3	0	2	0	1	0
Neutropenia
subjects affected / exposed	11 / 12 (91.67%)	62 / 83 (74.70%)	4 / 77 (5.19%)	26 / 33 (78.79%)	1 / 29 (3.45%)	36 / 50 (72.00%)	3 / 48 (6.25%)
occurrences all number	144	621	20	373	1	248	19
Thrombocytopenia
subjects affected / exposed	3 / 12 (25.00%)	16 / 83 (19.28%)	2 / 77 (2.60%)	8 / 33 (24.24%)	1 / 29 (3.45%)	8 / 50 (16.00%)	1 / 48 (2.08%)
occurrences all number	16	62	3	49	2	13	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	2 / 77 (2.60%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	2 / 48 (4.17%)
occurrences all number	1	1	2	1	0	0	2
Ear pain
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	2	0	2	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	1	0	1	0	0
Lacrimation increased
subjects affected / exposed	2 / 12 (16.67%)	3 / 83 (3.61%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	2 / 50 (4.00%)	0 / 48 (0.00%)
occurrences all number	3	3	0	1	0	2	0
Visual impairment
subjects affected / exposed	1 / 12 (8.33%)	4 / 83 (4.82%)	1 / 77 (1.30%)	1 / 33 (3.03%)	1 / 29 (3.45%)	3 / 50 (6.00%)	0 / 48 (0.00%)
occurrences all number	1	4	1	1	1	3	0
Cataract
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	2	2	0	1	0	1	0
Presbyopia
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	2 / 77 (2.60%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	2 / 48 (4.17%)
occurrences all number	1	0	2	0	0	0	2
Abdominal distension
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	2 / 77 (2.60%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	1	0	2	0	1	0	1
Abdominal pain
subjects affected / exposed	0 / 12 (0.00%)	7 / 83 (8.43%)	4 / 77 (5.19%)	7 / 33 (21.21%)	0 / 29 (0.00%)	0 / 50 (0.00%)	4 / 48 (8.33%)
occurrences all number	0	8	4	8	0	0	4
Abdominal pain upper
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	4 / 77 (5.19%)	1 / 33 (3.03%)	1 / 29 (3.45%)	1 / 50 (2.00%)	3 / 48 (6.25%)
occurrences all number	0	4	4	3	1	1	3
Constipation
subjects affected / exposed	3 / 12 (25.00%)	13 / 83 (15.66%)	7 / 77 (9.09%)	8 / 33 (24.24%)	4 / 29 (13.79%)	5 / 50 (10.00%)	3 / 48 (6.25%)
occurrences all number	4	20	10	11	5	9	5
Diarrhoea
subjects affected / exposed	6 / 12 (50.00%)	18 / 83 (21.69%)	9 / 77 (11.69%)	9 / 33 (27.27%)	2 / 29 (6.90%)	9 / 50 (18.00%)	7 / 48 (14.58%)
occurrences all number	10	31	10	19	2	12	8
Dry mouth
subjects affected / exposed	1 / 12 (8.33%)	3 / 83 (3.61%)	4 / 77 (5.19%)	2 / 33 (6.06%)	2 / 29 (6.90%)	1 / 50 (2.00%)	2 / 48 (4.17%)
occurrences all number	1	3	4	2	2	1	2
Dyspepsia
subjects affected / exposed	3 / 12 (25.00%)	4 / 83 (4.82%)	2 / 77 (2.60%)	1 / 33 (3.03%)	0 / 29 (0.00%)	3 / 50 (6.00%)	2 / 48 (4.17%)
occurrences all number	4	6	2	1	0	5	2
Flatulence
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	1 / 77 (1.30%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	2	1	2	0	0	1
Food poisoning
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	1 / 48 (2.08%)
occurrences all number	1	1	1	0	0	1	1
Chronic gastritis
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	1 / 77 (1.30%)	1 / 33 (3.03%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	3	1	1	1	1	0	0
Gingival pain
subjects affected / exposed	1 / 12 (8.33%)	4 / 83 (4.82%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	4 / 50 (8.00%)	0 / 48 (0.00%)
occurrences all number	1	4	0	0	0	4	0
Mouth ulceration
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	1 / 77 (1.30%)	2 / 33 (6.06%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	2	1	2	1	0	0
Nausea
subjects affected / exposed	6 / 12 (50.00%)	25 / 83 (30.12%)	11 / 77 (14.29%)	12 / 33 (36.36%)	7 / 29 (24.14%)	13 / 50 (26.00%)	4 / 48 (8.33%)
occurrences all number	8	48	13	22	9	26	4
Stomatitis
subjects affected / exposed	2 / 12 (16.67%)	10 / 83 (12.05%)	2 / 77 (2.60%)	5 / 33 (15.15%)	1 / 29 (3.45%)	5 / 50 (10.00%)	1 / 48 (2.08%)
occurrences all number	2	44	2	20	1	24	1
Rectal haemorrhage
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	1	0	1	0	0	0	1
Toothache
subjects affected / exposed	1 / 12 (8.33%)	6 / 83 (7.23%)	2 / 77 (2.60%)	1 / 33 (3.03%)	1 / 29 (3.45%)	5 / 50 (10.00%)	1 / 48 (2.08%)
occurrences all number	1	6	2	1	1	5	1
Vomiting
subjects affected / exposed	3 / 12 (25.00%)	15 / 83 (18.07%)	3 / 77 (3.90%)	9 / 33 (27.27%)	2 / 29 (6.90%)	6 / 50 (12.00%)	1 / 48 (2.08%)
occurrences all number	4	27	3	13	2	14	1
Oral disorder
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	1	0	0	0
Gastritis
subjects affected / exposed	0 / 12 (0.00%)	1 / 83 (1.20%)	4 / 77 (5.19%)	0 / 33 (0.00%)	2 / 29 (6.90%)	1 / 50 (2.00%)	2 / 48 (4.17%)
occurrences all number	0	1	5	0	2	1	3
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 12 (8.33%)	18 / 83 (21.69%)	2 / 77 (2.60%)	8 / 33 (24.24%)	1 / 29 (3.45%)	10 / 50 (20.00%)	1 / 48 (2.08%)
occurrences all number	1	20	3	9	2	11	1
Dermatitis contact
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	1	0	1	0	0
Dry skin
subjects affected / exposed	2 / 12 (16.67%)	6 / 83 (7.23%)	4 / 77 (5.19%)	2 / 33 (6.06%)	1 / 29 (3.45%)	4 / 50 (8.00%)	3 / 48 (6.25%)
occurrences all number	2	7	4	3	1	4	3
Hyperhidrosis
subjects affected / exposed	0 / 12 (0.00%)	4 / 83 (4.82%)	1 / 77 (1.30%)	1 / 33 (3.03%)	0 / 29 (0.00%)	3 / 50 (6.00%)	1 / 48 (2.08%)
occurrences all number	0	4	1	1	0	3	1
Ingrown hair
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Nail disorder
subjects affected / exposed	1 / 12 (8.33%)	5 / 83 (6.02%)	1 / 77 (1.30%)	3 / 33 (9.09%)	0 / 29 (0.00%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	1	5	1	3	0	2	1
Pain of skin
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	1	0	0	0
Pruritus
subjects affected / exposed	0 / 12 (0.00%)	5 / 83 (6.02%)	2 / 77 (2.60%)	1 / 33 (3.03%)	0 / 29 (0.00%)	4 / 50 (8.00%)	2 / 48 (4.17%)
occurrences all number	0	11	3	1	0	10	3
Rash
subjects affected / exposed	3 / 12 (25.00%)	7 / 83 (8.43%)	4 / 77 (5.19%)	3 / 33 (9.09%)	1 / 29 (3.45%)	4 / 50 (8.00%)	3 / 48 (6.25%)
occurrences all number	3	8	5	3	2	5	3
Skin disorder
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Skin swelling
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Swelling face
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	0	0	1	0
Night sweats
subjects affected / exposed	1 / 12 (8.33%)	3 / 83 (3.61%)	1 / 77 (1.30%)	1 / 33 (3.03%)	0 / 29 (0.00%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	1	4	1	2	0	2	1
Erythema
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	3 / 77 (3.90%)	0 / 33 (0.00%)	1 / 29 (3.45%)	3 / 50 (6.00%)	2 / 48 (4.17%)
occurrences all number	0	3	6	0	2	3	4
Renal and urinary disorders
Dysuria
subjects affected / exposed	3 / 12 (25.00%)	4 / 83 (4.82%)	2 / 77 (2.60%)	2 / 33 (6.06%)	2 / 29 (6.90%)	2 / 50 (4.00%)	0 / 48 (0.00%)
occurrences all number	3	4	2	2	2	2	0
Pollakiuria
subjects affected / exposed	1 / 12 (8.33%)	4 / 83 (4.82%)	1 / 77 (1.30%)	4 / 33 (12.12%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	5	1	5	1	0	0
Incontinence
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	1	0	1	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	1	0	1	0	0
Thyroid mass
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 12 (41.67%)	22 / 83 (26.51%)	14 / 77 (18.18%)	9 / 33 (27.27%)	5 / 29 (17.24%)	13 / 50 (26.00%)	9 / 48 (18.75%)
occurrences all number	12	49	29	23	8	26	21
Back pain
subjects affected / exposed	3 / 12 (25.00%)	17 / 83 (20.48%)	13 / 77 (16.88%)	6 / 33 (18.18%)	5 / 29 (17.24%)	11 / 50 (22.00%)	8 / 48 (16.67%)
occurrences all number	3	25	15	9	6	16	9
Bone pain
subjects affected / exposed	0 / 12 (0.00%)	10 / 83 (12.05%)	3 / 77 (3.90%)	6 / 33 (18.18%)	2 / 29 (6.90%)	4 / 50 (8.00%)	1 / 48 (2.08%)
occurrences all number	0	15	4	11	2	4	2
Joint swelling
subjects affected / exposed	2 / 12 (16.67%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	3	1	0	1	0	0	0
Muscle spasms
subjects affected / exposed	0 / 12 (0.00%)	5 / 83 (6.02%)	3 / 77 (3.90%)	1 / 33 (3.03%)	2 / 29 (6.90%)	4 / 50 (8.00%)	1 / 48 (2.08%)
occurrences all number	0	6	3	1	2	5	1
Musculoskeletal chest pain
subjects affected / exposed	2 / 12 (16.67%)	3 / 83 (3.61%)	3 / 77 (3.90%)	1 / 33 (3.03%)	2 / 29 (6.90%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	2	4	5	1	2	3	3
Musculoskeletal pain
subjects affected / exposed	1 / 12 (8.33%)	9 / 83 (10.84%)	5 / 77 (6.49%)	3 / 33 (9.09%)	3 / 29 (10.34%)	6 / 50 (12.00%)	2 / 48 (4.17%)
occurrences all number	1	19	7	10	3	9	4
Myalgia
subjects affected / exposed	1 / 12 (8.33%)	6 / 83 (7.23%)	3 / 77 (3.90%)	2 / 33 (6.06%)	0 / 29 (0.00%)	4 / 50 (8.00%)	3 / 48 (6.25%)
occurrences all number	1	8	3	4	0	4	3
Osteonecrosis of jaw
subjects affected / exposed	1 / 12 (8.33%)	3 / 83 (3.61%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	3 / 50 (6.00%)	0 / 48 (0.00%)
occurrences all number	1	3	0	0	0	3	0
Pain in extremity
subjects affected / exposed	3 / 12 (25.00%)	9 / 83 (10.84%)	7 / 77 (9.09%)	3 / 33 (9.09%)	1 / 29 (3.45%)	6 / 50 (12.00%)	6 / 48 (12.50%)
occurrences all number	4	18	8	5	1	13	7
Spinal pain
subjects affected / exposed	0 / 12 (0.00%)	5 / 83 (6.02%)	3 / 77 (3.90%)	1 / 33 (3.03%)	0 / 29 (0.00%)	4 / 50 (8.00%)	3 / 48 (6.25%)
occurrences all number	0	5	3	1	0	4	3
Temporomandibular joint syndrome
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Arthropathy
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Muscular weakness
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	1	0	1	1	0
Limb discomfort
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	2 / 77 (2.60%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	0	2	0	2	0	0
Osteoporosis
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	1 / 77 (1.30%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	2	1	2	0	0	1
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 12 (0.00%)	5 / 83 (6.02%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	3 / 50 (6.00%)	0 / 48 (0.00%)
occurrences all number	0	6	0	2	0	4	0
Bronchitis
subjects affected / exposed	1 / 12 (8.33%)	3 / 83 (3.61%)	2 / 77 (2.60%)	3 / 33 (9.09%)	1 / 29 (3.45%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	1	5	2	5	1	0	1
Cystitis
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	3 / 50 (6.00%)	1 / 48 (2.08%)
occurrences all number	0	3	1	0	0	3	1
Diverticulitis
subjects affected / exposed	0 / 12 (0.00%)	0 / 83 (0.00%)	2 / 77 (2.60%)	0 / 33 (0.00%)	2 / 29 (6.90%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	0	0	2	0	2	0	0
Ear infection
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	0 / 77 (0.00%)	2 / 33 (6.06%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	0	3	0	2	0	1	0
Gastroenteritis viral
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	1 / 48 (2.08%)
occurrences all number	1	1	1	0	0	1	1
Herpes zoster
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	3	1	1	0	1	1	0
Influenza
subjects affected / exposed	1 / 12 (8.33%)	8 / 83 (9.64%)	1 / 77 (1.30%)	4 / 33 (12.12%)	1 / 29 (3.45%)	4 / 50 (8.00%)	0 / 48 (0.00%)
occurrences all number	1	10	1	5	1	5	0
Localised infection
subjects affected / exposed	2 / 12 (16.67%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	1 / 12 (8.33%)	12 / 83 (14.46%)	7 / 77 (9.09%)	7 / 33 (21.21%)	3 / 29 (10.34%)	5 / 50 (10.00%)	4 / 48 (8.33%)
occurrences all number	3	16	11	8	4	8	7
Oral herpes
subjects affected / exposed	1 / 12 (8.33%)	3 / 83 (3.61%)	0 / 77 (0.00%)	3 / 33 (9.09%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	2	5	0	5	0	0	0
Pneumonia
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	2 / 77 (2.60%)	0 / 33 (0.00%)	2 / 29 (6.90%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	1	2	0	2	1	0
Sinusitis
subjects affected / exposed	2 / 12 (16.67%)	2 / 83 (2.41%)	2 / 77 (2.60%)	1 / 33 (3.03%)	2 / 29 (6.90%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	3	3	2	1	2	2	0
Skin infection
subjects affected / exposed	2 / 12 (16.67%)	2 / 83 (2.41%)	1 / 77 (1.30%)	2 / 33 (6.06%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	2	3	1	3	0	0	1
Tooth infection
subjects affected / exposed	2 / 12 (16.67%)	2 / 83 (2.41%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	2	2	0	1	0	1	0
Upper respiratory tract infection
subjects affected / exposed	3 / 12 (25.00%)	12 / 83 (14.46%)	2 / 77 (2.60%)	8 / 33 (24.24%)	2 / 29 (6.90%)	4 / 50 (8.00%)	0 / 48 (0.00%)
occurrences all number	8	15	2	11	2	4	0
Urinary tract infection
subjects affected / exposed	2 / 12 (16.67%)	9 / 83 (10.84%)	5 / 77 (6.49%)	6 / 33 (18.18%)	3 / 29 (10.34%)	3 / 50 (6.00%)	2 / 48 (4.17%)
occurrences all number	2	15	5	12	3	3	2
Herpes simplex
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	1 / 77 (1.30%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	1	2	1	2	0	0	1
Gingivitis
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	2	1	0	0	0	1	0
Rhinitis
subjects affected / exposed	2 / 12 (16.67%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	2	1	0	1	0	0	0
Cellulitis
subjects affected / exposed	0 / 12 (0.00%)	2 / 83 (2.41%)	2 / 77 (2.60%)	2 / 33 (6.06%)	1 / 29 (3.45%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	0	2	5	2	2	0	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 12 (25.00%)	17 / 83 (20.48%)	5 / 77 (6.49%)	9 / 33 (27.27%)	2 / 29 (6.90%)	8 / 50 (16.00%)	3 / 48 (6.25%)
occurrences all number	5	18	5	9	2	9	3
Diabetes mellitus
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	1 / 48 (2.08%)
occurrences all number	1	0	1	0	0	0	1
Hyperkalaemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	0 / 77 (0.00%)	0 / 33 (0.00%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 12 (0.00%)	4 / 83 (4.82%)	2 / 77 (2.60%)	2 / 33 (6.06%)	1 / 29 (3.45%)	2 / 50 (4.00%)	1 / 48 (2.08%)
occurrences all number	0	5	2	3	1	2	1
Hypokalaemia
subjects affected / exposed	1 / 12 (8.33%)	2 / 83 (2.41%)	1 / 77 (1.30%)	1 / 33 (3.03%)	1 / 29 (3.45%)	1 / 50 (2.00%)	0 / 48 (0.00%)
occurrences all number	1	2	1	1	1	1	0
Hyponatraemia
subjects affected / exposed	1 / 12 (8.33%)	0 / 83 (0.00%)	1 / 77 (1.30%)	0 / 33 (0.00%)	1 / 29 (3.45%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	0	1	0	1	0	0
Hyperuricaemia
subjects affected / exposed	0 / 12 (0.00%)	3 / 83 (3.61%)	2 / 77 (2.60%)	0 / 33 (0.00%)	1 / 29 (3.45%)	3 / 50 (6.00%)	1 / 48 (2.08%)
occurrences all number	0	3	2	0	1	3	1
Dehydration
subjects affected / exposed	1 / 12 (8.33%)	1 / 83 (1.20%)	0 / 77 (0.00%)	1 / 33 (3.03%)	0 / 29 (0.00%)	0 / 50 (0.00%)	0 / 48 (0.00%)
occurrences all number	1	1	0	1	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

31 Jul 2009

Due to the possible effect of administration of a high-fat meal on PD 0332991 exposure, a new guideline was added for subjects to fast from 1 hour before to 2 hours after administration of PD 0332991 on non-serial PK days. The list of prohibited drugs that might interact with CYP3A4 was updated.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: Phase 1/2, Open-Label, Randomized Study of the Safety, Efficacy, and Pharmacokinetics of Letrozole Plus PD 0332991 (Oral CDK 4/6 Inhibitor) and Letrozole Single Agent for the First-Line Treatment of ER Positive, HER2 Negative Advanced Breast Cancer in Postmenopausal Women

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1

Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1

Primary: Number of Subjects With Treatment-Related Adverse Events at Phase 1

Primary: Number of Subjects With Treatment-Related Adverse Events at Phase 1

Primary: Number of Subjects with Dose Limiting Toxicities (DLT) at Phase 1

Primary: Number of Subjects with Dose Limiting Toxicities (DLT) at Phase 1

Primary: Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment

Primary: Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment

Secondary: Objective Response Rate - Percentage of Subjects with Confirmed Objective Tumor Response at Phase 1

Secondary: Objective Response Rate - Percentage of Subjects with Confirmed Objective Tumor Response at Phase 1

Secondary: Percentage of Subjects With Clinical Benefit Response (CBR) at Phase 1

Secondary: Percentage of Subjects With Clinical Benefit Response (CBR) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC24) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC24) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-Life (t1/2) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-Life (t1/2) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1

Secondary: Summary of Plasma Palbociclib Steady-State Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1

Secondary: Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1

Secondary: Number of Subjects With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1

Secondary: Number of Subjects With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1

Secondary: Overall survival (OS) at Phase 2

Secondary: Overall survival (OS) at Phase 2

Secondary: Objective Response Rate - Percentage of Subjects With Confirmed Objective Response at Phase 2- Investigator Assessment

Secondary: Objective Response Rate - Percentage of Subjects With Confirmed Objective Response at Phase 2- Investigator Assessment

Secondary: Objective Response Rate - Percentage of Subjects with Confirmed Objective Response in Subjects With Measurable Disease at Phase 2- Investigator Assessment

Secondary: Objective Response Rate - Percentage of Subjects with Confirmed Objective Response in Subjects With Measurable Disease at Phase 2- Investigator Assessment

Secondary: Duration of Response at Phase 2 - Investigator Assessment

Secondary: Duration of Response at Phase 2 - Investigator Assessment

Secondary: Number of Subjects With CBR at Phase 2 - Investigator Assessment

Secondary: Number of Subjects With CBR at Phase 2 - Investigator Assessment

Secondary: Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment

Secondary: Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment

Secondary: Change from Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2

Secondary: Change from Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2

Secondary: Change from Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2

Secondary: Change from Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1

Secondary: Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1

Secondary: Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2

Secondary: Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2

Secondary: Percentage of Subjects With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2

Secondary: Percentage of Subjects With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2

Secondary: Number of Subjects with TEAEs (All Causalities) at Phase 2

Secondary: Number of Subjects with TEAEs (All Causalities) at Phase 2

Secondary: Number of Subjects with Treatment-Related Adverse Events at Phase 2

Secondary: Number of Subjects with Treatment-Related Adverse Events at Phase 2

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
Phase 1/2, Open-Label, Randomized Study of the Safety, Efficacy, and Pharmacokinetics of Letrozole Plus PD 0332991 (Oral CDK 4/6 Inhibitor) and Letrozole Single Agent for the First-Line Treatment of ER Positive, HER2 Negative Advanced Breast Cancer in Postmenopausal Women