Study Of Letrozole With Or Without Palbociclib (PD-0332991) For The First-Line Treatment Of Hormone-Receptor Positive Advanced Breast Cancer

• ClinicalTrials.gov Identifier: NCT00721409
• Recruitment Status: Completed
• First Posted: July 24, 2008
• Results First Posted: March 19, 2015
• Last Update Posted: November 4, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: PD 0332991; Drug: letrozole
• Enrollment: 177

Participant Flow

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

Arm/Group Title	Phase 1 (Palbociclib + Letrozole)	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)
Arm/Group Description	In Cycle 1 (3 weeks), participants 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), participants 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.	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.	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.
Period Title: Overall Study
Started	12	84	81
Treated	12	83	77
Completed	0	2	2
Not Completed	12	82	79
Reason Not Completed
Global deterioration of health status	2	6	3
Death	0	1	0
Randomized not Treated	0	1	4
Reason not specified	1	0	2
Adverse Event	0	13	2
Lost to Follow-up	0	0	1
Withdrawal by Subject	1	6	5
Objective progression or relapse	8	55	62

Baseline Characteristics

Arm/Group Title		Phase 1 (Palbociclib + Letrozole)	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Total
Arm/Group Description		In Cycle 1 (3 weeks), participants 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), participants 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.	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.	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.	Total of all reporting groups
Overall Number of Baseline Participants		12	84	81	177
Baseline Analysis Population Description		Analysis was done on participants who received at least one dose of study drug.
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	12 participants	84 participants	81 participants	177 participants
<18 Years		0 0.0%	0 0.0%	0 0.0%	0 0.0%
18-44 Years		1 8.3%	2 2.4%	4 4.9%	7 4.0%
45-64 Years		6 50.0%	45 53.6%	38 46.9%	89 50.3%
>= 65 Years		5 41.7%	37 44.0%	39 48.1%	81 45.8%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	84 participants	81 participants	177 participants
	Female	12 100.0%	84 100.0%	81 100.0%	177 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	84 participants	81 participants	177 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	6 7.1%	4 4.9%	10 5.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	1 1.2%	1 1.2%	2 1.1%
	White	11 91.7%	76 90.5%	72 88.9%	159 89.8%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	1 8.3%	1 1.2%	4 4.9%	6 3.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1
Description	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the 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.
Time Frame	Maximum treatment duration (approximately 55 months)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of any agent of the combination.

Arm/Group Title	Phase 1 (Palbociclib + Letrozole)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12
Measure Type: Number; Unit of Measure: Participants
Participants with AEs	12
Participants with SAEs	2
Participants with Grade 3 or 4 AEs	11
Participants with Grade 5 AEs	0

2. Primary Outcome

Title	Number of Participants With Treatment-Related Adverse Events at Phase 1
Description	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the 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.
Time Frame	Maximum treatment duration (approximately 55 months)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of any agent of the combination.

Arm/Group Title	Phase 1 (Palbociclib + Letrozole)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12
Measure Type: Number; Unit of Measure: Participants
Participants with AEs	12
Participants with SAEs	0
Participants with Grade 3 or 4 AEs	11
Participants with Grade 5 AEs	0

3. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities at Phase 1
Description	Dose limiting toxicity was defined as any of the following TEAEs occurring during the second cycle of treatment and possibly attributable to the combination of letrozole plus Palbociclib: 1. Grade 4 hematologic toxicity (including platelets <25,000/μL, ANC <500/μL). 2. Grade 3 neutropenia associated with a documented infection or fever ≥38.5°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 the next scheduled dose of either study treatment due to persisting treatment-related toxicities (platelet count <50,000/μL; ANC <1,000/μL; nonhematologic toxicities of Grade ≥3 severity). 5. Inability to deliver at least 80% of the planned Palbociclib or letrozole doses during Cycle 2 due to toxicity possibly attributable to the study treatment.
Time Frame	Cycle 2 (4 weeks)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of any agent of the combination.

Arm/Group Title	Phase 1 (Palbociclib + Letrozole)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12
Measure Type: Number; Unit of Measure: Participants
Grade 4 Neutropenia	2
<80% of doses due to elevated creatinine	1

4. Primary Outcome

Title	Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment
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).
Time Frame	From randomization date to date of first documentation of progression or death (assessed up to 41 months)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) was used. This represented all randomized participants from Ph2P1 or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	84	81	34	32	50	49
Median (95% Confidence Interval); Unit of Measure: Months
	20.2; (13.8 to 27.5)	10.2; (5.7 to 12.6)	26.1 [1]; (11.2 to NA)	5.7; (2.6 to 10.5)	18.1; (13.1 to 27.5)	11.1; (7.1 to 16.4)

[1]

Not reached

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Stratified analysis was presented above.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	1-sided p-value from the log-rank test stratified by stratification factors per randomization and Part.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.488
	Confidence Interval	(2-Sided) 95%; 0.319 to 0.748
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Unstratified analysis was presented above.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	1-sided p-value from the log-rank test.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.299
	Confidence Interval	(2-Sided) 95%; 0.156 to 0.572
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	The primary hypothesis to be tested was H0: λ=1 versus. HA: λ<1, where λ was the palbociclib plus letrozole:letrozole alone hazard ratio (HR). A HR less than 1 indicates a reduction in hazard rate in favor of Palbociclib + Letrozole. Unstratified analysis was presented above.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0046
	Comments	1-sided p-value from the log-rank test.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.508
	Confidence Interval	(2-Sided) 95%; 0.303 to 0.853
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1
Description	Percentage of participants 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.
Time Frame	From Baseline up to end of study (assessed up to 55 months)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment.

Arm/Group Title	Phase 1 (Palbociclib + Letrozole)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	33.3; (9.9 to 65.1)

6. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1
Description	CBR is 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.
Time Frame	From Baseline up to end of study (assessed up to 55 months)

Outcome Measure Data

Analysis Population Description

Efficacy analysis set included all enrolled participants with the disease under study, adequate baseline disease assessment, and who started study treatment.

Arm/Group Title	Phase 1 (Palbociclib + Letrozole)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	83.3; (51.6 to 97.9)

7. Secondary Outcome

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
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.
Time Frame	Cycle 1 Day 14, and Cycle 2 Day 14

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib Alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12	12
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng·hr/mL
	1982; (29%)	1933; (31%)

8. Secondary Outcome

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
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.
Time Frame	Cycle 1 Day 14, and Cycle 2 Day 14

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib Alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12	12
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	115.8; (28%)	108.4; (29%)

9. Secondary Outcome

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
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.
Time Frame	Cycle 1 Day 14, and Cycle 2 Day 14

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib Alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12	12
Median (Full Range); Unit of Measure: Hour
	7.92; (2.17 to 8.20)	7.92; (2.00 to 8.08)

10. Secondary Outcome

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
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.
Time Frame	Cycle 1 Day 14, and Cycle 2 Day 14

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib Alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12	12
Mean (Standard Deviation); Unit of Measure: Hour
	28.81 (5.0462)	NA [1] (NA)

[1]

Not calculated

11. Secondary Outcome

Title	Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1
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.
Time Frame	Cycle 1 Day 14, and Cycle 2 Day 14

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib Alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12	12
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: L/hr
	63.08; (2.17% to 8.20%)	NA [1]; (2.00% to 8.08%)

[1]

Not calculated

12. Secondary Outcome

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
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.
Time Frame	Cycle 1 Day 14, and Cycle 2 Day 14

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib Alone (Cycle 1 Day 14)	Palbociclib + Letrozole (Cycle 2 Day 14)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12	12
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: L
	2583; (2.17% to 8.20%)	NA [1]; (2.00% to 8.08%)

[1]

Not calculated

13. Secondary Outcome

Title	Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: AUC24 at Phase 1
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.
Time Frame	Cycle 2 Day 14, Cycle 2 Day 28

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib + Letrozole (Cycle 2 Day 14)	Letrozole Alone (Cycle 2 Day 28)
Arm/Group Description:	Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole.	Participants received daily 2.5 mg doses of letrozole alone.
Overall Number of Participants Analyzed	12	12
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng·hr/mL
	1739; (2.17% to 8.20%)	1936; (2.00% to 8.08%)

14. Secondary Outcome

Title	Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Cmax at Phase 1
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.
Time Frame	Cycle 2 Day 14, and Cycle 2 Day 28

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib + Letrozole (Cycle 2 Day 14)	Letrozole Alone (Cycle 2 Day 28)
Arm/Group Description:	Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole.	Participants received daily 2.5 mg doses of letrozole alone.
Overall Number of Participants Analyzed	12	12
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	94.95; (2.17% to 8.20%)	104.0; (2.00% to 8.08%)

15. Secondary Outcome

Title	Summary of Plasma Letrozole Pharmacokinetic Parameter Following Letrozole Alone and in Combination With Palbociclib: Tmax at Phase 1
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.
Time Frame	Cycle 2 Day 14, and Cycle 2 Day 28

Outcome Measure Data

Analysis Population Description

The pharmacokinetic concentration set included all participants who were treated and had at least 1 concentration measurement in at least 1 pharmacokinetic assessment day. The pharmacokinetic parameter analysis set consisted of all participants treated who had at least 1 of the pharmacokinetic parameters of primary interest.

Arm/Group Title	Palbociclib + Letrozole (Cycle 2 Day 14)	Letrozole Alone (Cycle 2 Day 28)
Arm/Group Description:	Participants received 125 mg oral doses of palbociclib with daily 2.5 mg doses of letrozole.	Participants received daily 2.5 mg doses of letrozole alone.
Overall Number of Participants Analyzed	12	12
Median (Full Range); Unit of Measure: Hour
	2.00; (0.833 to 4.13)	1.04; (0.00 to 4.42)

16. Secondary Outcome

Title	Number of Participants With Increase From Baseline in Corrected QT (QTc) Interval at Phase 1
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). Participants with maximum increase from baseline of 30 to less than (<) 60 msec(borderline) and greater than or equal to (>=) 60 msec (prolonged) were summarized.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of any agent of the combination.

Arm/Group Title	Phase 1 (Palbociclib + Letrozole)
Arm/Group Description:	In Cycle 1 (3 weeks), participants 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), participants 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.
Overall Number of Participants Analyzed	12
Measure Type: Number; Unit of Measure: Participants
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

17. Secondary Outcome

Title	Overall Survival (OS) at Phase 2
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.
Time Frame	From randomization until death (assessed up to 86 months)

Outcome Measure Data

Analysis Population Description

ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	84	81	34	32	50	49
Median (95% Confidence Interval); Unit of Measure: Months
	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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	Stratified analysis was presented above. Hazard ratio was assuming proportional hazards, a hazard ratio less than 1 indicated a reduction in hazard rate in favor of palbociclib + letrozole.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2812
	Comments	1-sided p-value from the log-rank test stratified by Part (α = 0.10).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.897
	Confidence Interval	(2-Sided) 95%; 0.623 to 1.294
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	Unstratified analysis was presented above.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2803
	Comments	1-sided p-value from the unstratified log-rank test (α=0.10).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.837
	Confidence Interval	(2-Sided) 95%; 0.458 to 1.527
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	Unstratified analysis was presented above.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3875
	Comments	1-sided p-value from the unstratified log-rank test (α=0.10).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.935
	Confidence Interval	(2-Sided) 95%; 0.590 to 1.480
	Estimation Comments	[Not Specified]

18. Secondary Outcome

Title	Objective Response Rate - Percentage of Participants With Confirmed Objective Response at Phase 2- Investigator Assessment
Description	Percentage of participants with objective response based assessment of confirmed CR or confirmed 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.
Time Frame	From randomization up to the end of treatment (approximately 41 months)

Outcome Measure Data

Analysis Population Description

ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	84	81	34	32	50	49
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1347
	Comments	1-sided p-value is from the stratified exact test (1-sided, α =0.10)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.97
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0849
	Comments	Chi-square test was used (1-sided, α=0.10)
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.37
	Confidence Interval	(2-Sided) 95%; 0.74 to 7.84
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4515
	Comments	Chi-square test was used (1-sided, α=0.10)
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.48 to 2.76
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Objective Response Rate - Percentage of Participants With Confirmed Objective Response in Participants With Measurable Disease at Phase 2- Investigator Assessment
Description	Percentage of participants 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 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. Measurable disease referred to the lesions that was 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 (depending on reconstruction interval). Clinical lesions were only be considered measurable when they were superficial (eg, skin nodules, palpable lymph nodes).
Time Frame	From randomization up to the end of treatment (approximately 41 months)

Outcome Measure Data

Analysis Population Description

Participants in ITT population with measurable disease were used.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	65	66	27	23	21	43
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0471
	Comments	1-sided p-value is from the stratified exact test (1-sided, α =0.10)
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.93
	Confidence Interval	(2-Sided) 95%; 0.91 to 4.08
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1180
	Comments	Chi-square test was used (1-sided, α=0.10)
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.34
	Confidence Interval	(2-Sided) 95%; 0.65 to 8.66
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1631
	Comments	Chi-square test was used (1-sided, α=0.10)
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.72
	Confidence Interval	(2-Sided) 95%; 0.65 to 4.54
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Duration of Response at Phase 2 - Investigator Assessment
Description	Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP 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 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per RECIST).
Time Frame	From randomization up to the end of treatment (approximately 41 months)

Outcome Measure Data

Analysis Population Description

A subset of ITT population i.e., participants who had response was used for this analysis.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	36	27	15	8	21	19
Median (95% Confidence Interval); Unit of Measure: Months
	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 [1]; (13.0 to NA)	14.8 [1]; (7.4 to NA)

[1]

Not reached

21. Secondary Outcome

Title	Number of Participants With CBR at Phase 2 - Investigator Assessment
Description	CBR is 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.
Time Frame	From randomization up to the end of treatment (approximately 41 months)

Outcome Measure Data

Analysis Population Description

ITT was used. This represented all randomized patients from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	84	81	34	32	50	49
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	1-sided p-value is from the stratified exact test (1-sided, α =0.10).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.18
	Confidence Interval	(2-Sided) 95%; 1.48 to 6.98
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0065
	Comments	Chi-square test was used (1-sided, α=0.10)
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.18
	Confidence Interval	(2-Sided) 95%; 1.30 to 13.90
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	Unstratified analysis was presented above. Exact CI was based on Clopper-Pearson method.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0442
	Comments	Chi-square test was used (1-sided, α=0.10)
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.55
	Confidence Interval	(2-Sided) 95%; 0.89 to 7.70
	Estimation Comments	[Not Specified]

22. Secondary Outcome

Title	Time to Tumor Progression (TTP) at Phase 2-Investigator Assessment
Description	Time in weeks, (months or years) from randomization or (start of study treatment for non-randomized studies) to first documentation of objective tumor progression. TTP 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 7 or 30.44 if in months. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD] per RECIST).
Time Frame	From randomization up to the end of treatment (approximately 41 months)

Outcome Measure Data

Analysis Population Description

ITT was used. This represented all randomized participants from Ph2P1or Ph2P2 or Ph2P1+Ph2P2, where participants were classified according to the randomized treatment regardless of what treatment, if any, was received.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	84	81	34	32	50	49
Median (95% Confidence Interval); Unit of Measure: Months
	20.2; (13.8 to 27.5)	10.2; (5.7 to 12.6)	26.1 [1]; (11.2 to NA)	5.7; (2.6 to 10.5)	18.8; (13.1 to 27.5)	11.1; (7.1 to 16.4)

[1]

Not reached

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	Kaplan-Meier method was applied for median and 95% CI. Hazard ratio was based on assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of palbociclib + letrozole.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	1-sided p-value is from the stratified log-rank test (α =0.10).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.399
	Confidence Interval	(2-Sided) 95%; 0.265 to 0.601
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	1-sided p-value is from unstratified log-rank test (α=0.10).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.299
	Confidence Interval	(2-Sided) 95%; 0.156 to 0.572
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	Unstratified analysis was presented above. Kaplan-Meier method was applied for median and 95% CI.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0030
	Comments	1-sided p-value is from unstratified log-rank test (α=0.10).
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.486
	Confidence Interval	(2-Sided) 95%; 0.288 to 0.822
	Estimation Comments	[Not Specified]

23. Secondary Outcome

Title	Change From Baseline in Modified Brief Pain Inventory in Pain Severity Scale (mBPI-sf) Questionnaire at Phase 2
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, 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").
Time Frame	Baseline, End of treatment (approximately 41 months)

Outcome Measure Data

Analysis Population Description

Patient reported outcome evaluable participants included participants who had received at least 1 dose of study medication, had baseline data, and at least one post-baseline measurement.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	76	74	29	27	47	47
Mean (Standard Error); Unit of Measure: Units on a scale
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	Statistical analysis presented above is for Pain Severity Scale.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6900
	Comments	P-values are based on 2-sample t-test.
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.7 to 1.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	Statistical analysis presented above is for Pain Severity Scale.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7125
	Comments	P-values are based on 2-sample t-test.
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -1.8 to 1.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	Statistical analysis presented above is for Pain Severity Scale.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4012
	Comments	P-values are based on 2-sample t-test.
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -0.6 to 1.5
	Estimation Comments	[Not Specified]

24. Secondary Outcome

Title	Change From Baseline in Modified Brief Pain Inventory in Pain Interference Scale (mBPI-sf) Questionnaire at Phase 2
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, 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").
Time Frame	Baseline, End of treatment (approximately 41 months)

Outcome Measure Data

Analysis Population Description

Patient reported outcome evaluable participants included participants who had received at least 1 dose of study medication, had baseline data, and at least one post-baseline measurement.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	76	74	29	27	47	47
Mean (Standard Error); Unit of Measure: Units on a scale
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2 (Palbociclib + Letrozole), Phase 2 (Letrozole)
	Comments	Statistical analysis presented above is for Pain Interference Scale.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3346
	Comments	P-values are based on 2-sample t-test.
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -0.5 to 1.3
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ph2P1 (Palbociclib + Letrozole), Ph2P1 (Letrozole)
	Comments	Statistical analysis presented above is for Pain Interference Scale.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5630
	Comments	P-values are based on 2-sample t-test.
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -1.0 to 1.9
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ph2P2 (Palbociclib + Letrozole), Ph2P2 (Letrozole)
	Comments	Statistical analysis presented above is for Pain Severity Scale.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4427
	Comments	P-values are based on 2-sample t-test.
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -0.7 to 1.6
	Estimation Comments	[Not Specified]

25. Secondary Outcome

Title	Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - p16/INK4A, CCND1
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 participant 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.
Time Frame	Screening visit (≤ 28 Days prior to dosing)

Outcome Measure Data

Analysis Population Description

Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments.

Arm/Group Title	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	22	24	50	48
Measure Type: Number; Unit of Measure: Participants
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

26. Secondary Outcome

Title	Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Ki67
Description	Frequency of tumor tissue biomarker Ki67 was evaluated in across treatment groups.
Time Frame	Screening visit (≤ 28 Days prior to dosing)

Outcome Measure Data

Analysis Population Description

All participants in the Safety Analysis set who had a Ki67 protein biomarker assessment.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	74	71	24	26	50	45
Measure Type: Number; Unit of Measure: Participants
<=20%	26	31	7	16	19	15
>20%	48	40	17	10	31	30

27. Secondary Outcome

Title	Presence or Absence of Tumor Tissue Biomarkers at Phase 2 - Tumor Retinoblastoma (RB) and CyclinD1
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.
Time Frame	Screening visit (≤ 28 Days prior to dosing)

Outcome Measure Data

Analysis Population Description

Protein biomarkers analysis set included all participants in the safety analysis set who had at least protein biomarker assessment.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	45	35	12	16	33	19
Measure Type: Number; Unit of Measure: Participants
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

28. Secondary Outcome

Title	Summary of Copy Number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) at Phase 2
Description	Gene copy number for CCND1 (CCND1/CEP11) and p16/INK4A (p16/CEP9) were evaluated. This analysis was done for Phase 2 combined group.
Time Frame	Screening visit (≤ 28 Days prior to dosing)

Outcome Measure Data

Analysis Population Description

Copy number analysis set included participants in the Safety Analysis Set who had at least 1 of the biomarker assessments.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)
Arm/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.	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.
Overall Number of Participants Analyzed	72	72
Mean (Standard Deviation); Unit of Measure: Copy number
CCND1	2.76 (1.875)	2.73 (1.559)
p16/INK4A	0.83 (0.224)	0.87 (0.173)

29. Secondary Outcome

Title	Percentage of Participants With Tumor Expression of CYP19A1 and CCND1 Genotypes at Phase 2
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.
Time Frame	Screening visit (≤ 28 Days prior to dosing)

Outcome Measure Data

Analysis Population Description

Polymorphism analysis set included participants in the safety analysis set who had at least 1 polymorphism assessment.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	76	74	30	28	46	46
Measure Type: Number; Unit of Measure: Percentage of participants
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

30. Secondary Outcome

Title	Number of Participants With TEAEs (All Causalities) at Phase 2
Description	AE:any untoward medical occurrence in participant 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 and jeopardized participants or required treatment to prevent other AE outcomes 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 that were absent before treatment or worsened relative to pre-treatment state.AEs were graded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and coded using Medical Dictionary for Regulatory Activities (MedDRA). Participants with AE of grade 3 or 4 and grade 5 were reported as Grade 3:Severe, Grade 4:Life threatening, Grade 5:Death related to AE.
Time Frame	Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)

Outcome Measure Data

Analysis Population Description

All treated as treated set included all treated participants classified by the treatment actually received.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	83	77	33	29	50	48
Measure Type: Count of Participants; Unit of Measure: Participants
Participants with AEs	83 100.0%	66 85.7%	33 100.0%	25 86.2%	50 100.0%	41 85.4%
Participants with SAEs	22 26.5%	6 7.8%	10 30.3%	2 6.9%	12 24.0%	4 8.3%
Participants with Grade 3 or 4 AEs	70 84.3%	19 24.7%	29 87.9%	5 17.2%	41 82.0%	14 29.2%
Participants with Grade 5 AEs	1 1.2%	0 0.0%	0 0.0%	0 0.0%	1 2.0%	0 0.0%

31. Secondary Outcome

Title	Number of Participants With Treatment-Related Adverse Events at Phase 2
Description	AE: any untoward medical occurrence in a participant who received study drug. AEs included both serious and non-serious adverse events. SAE: AE resulting in any of the 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 that were absent before treatment or that worsened relative to pre-treatment state. Treatment related AEs: all AEs with causality related to treatment. Relatedness to drug was assessed by the investigator. AEs were graded according to the CTCAE version 3.0 and coded using the MedDRA. Number of participants with AE of grade 3 or 4 and with AE of grade 5 were reported as Grade 3: Severe, Grade 4: Life threatening, Grade 5: Death related to AE.
Time Frame	Baseline up to 28 days after last dose of study drug (for a maximum of 86 months)

Outcome Measure Data

Analysis Population Description

All treated as treated set included all treated participants classified by the treatment actually received.

Arm/Group Title	Phase 2 (Palbociclib + Letrozole)	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letrozole)	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letrozole)	Ph2P2 (Letrozole)
Arm/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.	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.	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.	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.	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.	Participants were randomized to receive Letrozole. Letrozole 2.5 mg/d was administered orally in a continuous regimen. This was considered as control arm.
Overall Number of Participants Analyzed	83	77	33	29	50	48
Measure Type: Count of Participants; Unit of Measure: Participants
Participants with AEs	78 94.0%	33 42.9%	32 97.0%	13 44.8%	46 92.0%	20 41.7%
Participants with SAEs	1 1.2%	0 0.0%	0 0.0%	0 0.0%	1 2.0%	0 0.0%
Participants with Grade 3 or 4 AEs	57 68.7%	2 2.6%	25 75.8%	0 0.0%	32 64.0%	2 4.2%
Participants with Grade 5 AEs	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Adverse Events

Time Frame

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

Adverse Event Reporting Description

An event may be categorized as serious in one participant and non serious in another participant, or one participant may experience both serious and non serious event. All treatment emergent AEs and SAEs were collected and reported. The same event may appear as both AE and SAE. All-cause mortality data included all anticipated and unanticipated deaths due to any cause. Analysis was done on participants who received at least one dose of study drug.

Arm/Group Title

Phase 1 (Palbociclib + Letrozole)

Phase 2 (Palbociclib + Letrozole)

Phase 2 (Letrozole)

Ph2P1 (Palbociclib + Letrozole)

Ph2P1 (Letrozole)

Ph2P2 (Palbociclib + Letrozole)

Ph2P2 (Letrozole)

Arm/Group Description

In Cycle 1 (3 weeks), participants 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), participants 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.

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.

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.

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.

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.

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.

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

All-Cause Mortality

Phase 1 (Palbociclib + Letrozole)

Phase 2 (Palbociclib + Letrozole)

Phase 2 (Letrozole)

Ph2P1 (Palbociclib + Letrozole)

Ph2P1 (Letrozole)

Ph2P2 (Palbociclib + Letrozole)

Ph2P2 (Letrozole)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Total

0/12 (0.00%)

3/83 (3.61%)

1/77 (1.30%)

1/33 (3.03%)

0/29 (0.00%)

2/50 (4.00%)

1/48 (2.08%)

Serious Adverse Events

Phase 1 (Palbociclib + Letrozole)

Phase 2 (Palbociclib + Letrozole)

Phase 2 (Letrozole)

Ph2P1 (Palbociclib + Letrozole)

Ph2P1 (Letrozole)

Ph2P2 (Palbociclib + Letrozole)

Ph2P2 (Letrozole)

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

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%)

Blood and lymphatic system disorders

Anaemia * 1

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%)

Cardiac disorders

Cardiac failure * 1

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%)

Gastrointestinal disorders

Abdominal pain * 1

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%)

Colitis ischaemic * 1

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%)

Diarrhoea * 1

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%)

Gastrointestinal disorder * 1

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%)

Ileus * 1

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%)

Oesophageal achalasia * 1

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%)

Nausea * 1

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%)

Vomiting * 1

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%)

Gastritis * 1

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%)

Inguinal hernia * 1

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%)

General disorders

Asthenia * 1

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%)

Chest pain * 1

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%)

Disease progression * 1

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%)

Pain * 1

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%)

Infections and infestations

Erysipelas * 1

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%)

Gangrene * 1

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%)

Influenza * 1

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%)

Pneumonia * 1

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%)

Staphylococcal bacteraemia * 1

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%)

Upper respiratory tract infection * 1

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%)

Campylobacter infection * 1

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%)

Infective exacerbation of chronic obstructive airways disease * 1

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%)

Mastoiditis * 1

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%)

Injury, poisoning and procedural complications

Fractured sacrum * 1

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%)

Hip fracture * 1

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%)

Humerus fracture * 1

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%)

Upper limb fracture * 1

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%)

Investigations

Alanine aminotransferase increased * 1

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%)

Aspartate aminotransferase increased * 1

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%)

Blood alkaline phosphatase increased * 1

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%)

Gamma-glutamyltransferase increased * 1

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%)

Musculoskeletal and connective tissue disorders

Back pain * 1

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%)

Bone pain * 1

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%)

Intervertebral disc protrusion * 1

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%)

Arthralgia * 1

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%)

Osteonecrosis of jaw * 1

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%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Fallopian tube cancer * 1

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%)

Plasma cell myeloma * 1

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%)

Nervous system disorders

Neuralgia * 1

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%)

Brain stem infarction * 1

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%)

Renal and urinary disorders

Nephrolithiasis * 1

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%)

Renal disorder * 1

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%)

Urethral obstruction * 1

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%)

Acute kidney injury * 1

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%)

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism * 1

1/12 (8.33%)

4/83 (4.82%)

0/77 (0.00%)

4/33 (12.12%)

0/29 (0.00%)

0/50 (0.00%)

0/48 (0.00%)

Dyspnoea * 1

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%)

Skin and subcutaneous tissue disorders

Subcutaneous emphysema * 1

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%)

1 Term from vocabulary, MedDRA (v20.1); * Indicates events were collected by non-systematic assessment

Other (Not Including Serious) Adverse Events

Frequency Threshold for Reporting Other Adverse Events

5%

Phase 1 (Palbociclib + Letrozole)

Phase 2 (Palbociclib + Letrozole)

Phase 2 (Letrozole)

Ph2P1 (Palbociclib + Letrozole)

Ph2P1 (Letrozole)

Ph2P2 (Palbociclib + Letrozole)

Ph2P2 (Letrozole)

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

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%)

Blood and lymphatic system disorders

Anaemia * 1

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%)

Leukopenia * 1

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%)

Lymphopenia * 1

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%)

Neutropenia * 1

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%)

Thrombocytopenia * 1

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%)

Ear and labyrinth disorders

Vertigo * 1

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%)

Ear pain * 1

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%)

Endocrine disorders

Hyperthyroidism * 1

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%)

Thyroid mass * 1

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%)

Eye disorders

Dry eye * 1

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%)

Lacrimation increased * 1

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%)

Visual impairment * 1

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%)

Cataract * 1

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%)

Presbyopia * 1

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%)

Gastrointestinal disorders

Abdominal discomfort * 1

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%)

Abdominal distension * 1

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%)

Abdominal pain * 1

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%)

Abdominal pain upper * 1

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%)

Constipation * 1

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%)

Diarrhoea * 1

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%)

Dry mouth * 1

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%)

Dyspepsia * 1

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%)

Flatulence * 1

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%)

Food poisoning * 1

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%)

Chronic gastritis * 1

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%)

Gastrooesophageal reflux disease * 1

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%)

Gingival pain * 1

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%)

Mouth ulceration * 1

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%)

Nausea * 1

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%)

Stomatitis * 1

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%)

Rectal haemorrhage * 1

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%)

Toothache * 1

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%)

Vomiting * 1

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%)

Oral disorder * 1

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%)

Gastritis * 1

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%)

General disorders

Asthenia * 1

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%)

Chest pain * 1

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%)

Facial pain * 1

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%)

Fatigue * 1

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%)

Influenza like illness * 1

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%)

Mucosal inflammation * 1

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%)

Non-cardiac chest pain * 1

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%)

Oedema peripheral * 1

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%)

Pain * 1

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%)

Pyrexia * 1

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%)

Temperature intolerance * 1

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%)

Chills * 1

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%)

Face oedema * 1

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%)

Peripheral swelling * 1

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%)

Immune system disorders

Seasonal allergy * 1

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%)

Infections and infestations

Conjunctivitis * 1

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%)

Bronchitis * 1

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%)

Cystitis * 1

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%)

Diverticulitis * 1

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%)

Ear infection * 1

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%)

Gastroenteritis viral * 1

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%)

Herpes zoster * 1

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%)

Influenza * 1

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%)

Localised infection * 1

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%)

Nasopharyngitis * 1

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%)

Oral herpes * 1

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%)

Pneumonia * 1

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%)

Sinusitis * 1

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%)

Skin infection * 1

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%)

Tooth infection * 1

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%)

Upper respiratory tract infection * 1

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%)

Urinary tract infection * 1

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%)

Herpes simplex * 1

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%)

Gingivitis * 1

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%)

Rhinitis * 1

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%)

Cellulitis * 1

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%)

Injury, poisoning and procedural complications

Contusion * 1

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%)

Thermal burn * 1

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%)

Fall * 1

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%)

Periorbital haemorrhage * 1

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%)

Skin abrasion * 1

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%)

Skin injury * 1

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%)

Investigations

Alanine aminotransferase increased * 1

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%)

Aspartate aminotransferase increased * 1

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%)

Blood alkaline phosphatase increased * 1

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%)

Blood creatinine increased * 1

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%)

Blood phosphorus decreased * 1

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%)

Gamma-glutamyltransferase increased * 1

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%)

Red blood cell count decreased * 1

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%)

Weight decreased * 1

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%)

White blood cell count decreased * 1

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%)

Weight increased * 1

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%)

Metabolism and nutrition disorders

Decreased appetite * 1

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%)

Diabetes mellitus * 1

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%)

Hyperkalaemia * 1

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%)

Hypocalcaemia * 1

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%)

Hypokalaemia * 1

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%)

Hyponatraemia * 1

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%)

Hyperuricaemia * 1

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%)

Dehydration * 1

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%)

Musculoskeletal and connective tissue disorders

Arthralgia * 1

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%)

Back pain * 1

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%)

Bone pain * 1

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%)

Joint swelling * 1

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%)

Muscle spasms * 1

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%)

Musculoskeletal chest pain * 1

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%)

Musculoskeletal pain * 1

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%)

Myalgia * 1

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%)

Osteonecrosis of jaw * 1

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%)

Pain in extremity * 1

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%)

Spinal pain * 1

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%)

Temporomandibular joint syndrome * 1

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%)

Arthropathy * 1

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%)

Muscular weakness * 1

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%)

Limb discomfort * 1

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%)

Osteoporosis * 1

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%)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Tumour pain * 1

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%)

Nervous system disorders

Dizziness * 1

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%)

Dysgeusia * 1

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%)

Headache * 1

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%)

Memory impairment * 1

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%)

Neuropathy peripheral * 1

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%)

Paraesthesia * 1

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%)

Sciatica * 1

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%)

Sinus headache * 1

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%)

Syncope * 1

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%)

Radicular pain * 1

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%)

Peripheral sensory neuropathy * 1

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%)

Psychiatric disorders

Anxiety * 1

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%)

Depression * 1

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%)

Insomnia * 1

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%)

Mood altered * 1

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%)

Sleep disorder * 1

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%)

Renal and urinary disorders

Dysuria * 1

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%)

Pollakiuria * 1

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%)

Incontinence * 1

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%)

Reproductive system and breast disorders

Breast discomfort * 1

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%)

Breast pain * 1

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%)

Pelvic pain * 1

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%)

Vaginal discharge * 1

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%)

Vulvovaginal pruritus * 1

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%)

Respiratory, thoracic and mediastinal disorders

Cough * 1

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%)

Dyspnoea * 1

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%)

Epistaxis * 1

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%)

Nasal congestion * 1

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%)

Oropharyngeal pain * 1

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%)

Rhinitis allergic * 1

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%)

Rhinorrhoea * 1

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%)

Sinus congestion * 1

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%)

Snoring * 1

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%)

Lower respiratory tract congestion * 1

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%)

Skin and subcutaneous tissue disorders

Alopecia * 1

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%)

Dermatitis contact * 1

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%)

Dry skin * 1

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%)

Hyperhidrosis * 1

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%)

Ingrown hair * 1

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%)

Nail disorder * 1

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%)

Pain of skin * 1

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%)

Pruritus * 1

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%)

Rash * 1

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%)

Skin disorder * 1

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%)

Skin swelling * 1

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%)

Swelling face * 1

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%)

Night sweats * 1

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%)

Erythema * 1

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%)

Vascular disorders

Haematoma * 1

0/12 (0.00%)

0

2/83 (2.41%)

0/77 (0.00%)

2/33 (6.06%)

0/29 (0.00%)

0/50 (0.00%)

0/48 (0.00%)

Hot flush * 1

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%)

Hypertension * 1

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%)

Lymphoedema * 1

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%)

Peripheral vascular disorder * 1

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%)

Phlebitis * 1

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%)

1 Term from vocabulary, MedDRA (v20.1); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Finn RS, Rugo HS, Gelmon KA, Cristofanilli M, Colleoni M, Loi S, Schnell P, Lu DR, Theall KP, Mori A, Gauthier E, Bananis E, Turner NC, Dieras V. Long-Term Pooled Safety Analysis of Palbociclib in Combination with Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Updated Analysis with up to 5 Years of Follow-Up. Oncologist. 2021 May;26(5):e749-e755. doi: 10.1002/onco.13684. Epub 2021 Mar 10.

Finn RS, Boer K, Bondarenko I, Patel R, Pinter T, Schmidt M, Shparyk YV, Thummala A, Voitko N, Bananis E, McRoy L, Wilner K, Huang X, Kim S, Slamon DJ, Ettl J. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1, TRIO-18). Breast Cancer Res Treat. 2020 Sep;183(2):419-428. doi: 10.1007/s10549-020-05755-7. Epub 2020 Jul 18.

Ettl J, Im SA, Ro J, Masuda N, Colleoni M, Schnell P, Bananis E, Lu DR, Cristofanilli M, Rugo HS, Finn RS. Hematologic adverse events following palbociclib dose reduction in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: pooled analysis from randomized phase 2 and 3 studies. Breast Cancer Res. 2020 Mar 12;22(1):27. doi: 10.1186/s13058-020-01263-0.

Rugo HS, Turner NC, Finn RS, Joy AA, Verma S, Harbeck N, Masuda N, Im SA, Huang X, Kim S, Sun W, Iyer S, Schnell P, Bartlett CH, Johnston S. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018 Sep;101:123-133. doi: 10.1016/j.ejca.2018.05.017. Epub 2018 Jul 25.

Dieras V, Rugo HS, Schnell P, Gelmon K, Cristofanilli M, Loi S, Colleoni M, Lu DR, Mori A, Gauthier E, Huang Bartlett C, Slamon DJ, Turner NC, Finn RS. Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer. J Natl Cancer Inst. 2019 Apr 1;111(4):419-430. doi: 10.1093/jnci/djy109.

Wedam SB, Beaver JA, Amiri-Kordestani L, Bloomquist E, Tang S, Goldberg KB, Sridhara R, Ibrahim A, Kim G, Kluetz P, McKee A, Pazdur R. US Food and Drug Administration Pooled Analysis to Assess the Impact of Bone-Only Metastatic Breast Cancer on Clinical Trial Outcomes and Radiographic Assessments. J Clin Oncol. 2018 Apr 20;36(12):1225-1231. doi: 10.1200/JCO.2017.74.6917. Epub 2018 Mar 9.

Bell T, Crown JP, Lang I, Bhattacharyya H, Zanotti G, Randolph S, Kim S, Huang X, Huang Bartlett C, Finn RS, Slamon D. Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment. Curr Med Res Opin. 2016 May;32(5):959-65. doi: 10.1185/03007995.2016.1157060. Epub 2016 Mar 2.

Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. Epub 2014 Dec 16.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00721409
• Other Study ID Numbers: A5481003; 2008-002392-27 ( EudraCT Number )
• First Submitted: July 22, 2008
• First Posted: July 24, 2008
• Results First Submitted: March 4, 2015
• Results First Posted: March 19, 2015
• Last Update Posted: November 4, 2019