Trial Outcomes & Findings for Palbociclib Pharmacokinetics Study In Postmenopausal Chinese Women With ER (+), HER2 (-) Advanced Breast Cancer (NCT NCT02499146)

NCT ID: NCT02499146

Last Updated: 2025-12-19

Results Overview

AUC10 for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 26 participants
• Primary outcome timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, and 10 hours post dose
• Results posted on: 2025-12-19

Participant Flow

Participant milestones

Measure	Palbociclib + Letrozole Participants received a single dose of palbociclib 125 milligrams (mg) orally on Day 1 during the 5-day lead-in phase and received once daily (QD) from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Overall Study STARTED	26
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	26

Reasons for withdrawal

Measure	Palbociclib + Letrozole Participants received a single dose of palbociclib 125 milligrams (mg) orally on Day 1 during the 5-day lead-in phase and received once daily (QD) from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Overall Study Global deterioration of health status	1
Overall Study Objective progression or relapse	20
Overall Study Other	2
Overall Study Participant refused continued treatment for reason other than adverse event	3

Baseline Characteristics

Palbociclib Pharmacokinetics Study In Postmenopausal Chinese Women With ER (+), HER2 (-) Advanced Breast Cancer

Baseline characteristics by cohort

Measure	Palbociclib + Letrozole n=26 Participants Participants received palbociclib 125 milligrams (mg) orally once daily (QD) on Day 1 during the 5-day lead-in phase and from Day 1 to Day 21 (followed by 7 days off-treatment) during each treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 was started with Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Age, Continuous	50.8 years STANDARD_DEVIATION 7.6 • n=8 Participants
Sex: Female, Male Female	26 Participants n=8 Participants
Sex: Female, Male Male	0 Participants n=8 Participants
Race/Ethnicity, Customized Asian	26 Participants n=8 Participants

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

Cmax of palbociclib in the single-dose part (lead-in phase) was observed directly from data.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) for Palbociclib

82.14 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 25

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

Tmax for palbociclib in the single-dose part (lead-in phase) was observed directly from data as time of first occurrence.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: Time to Reach Maximum Plasma Concentration (Tmax) for Palbociclib

7.94 hours Interval 3.97 to 10.0

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, and 10 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

AUC10 for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to the Time 10 Hours (AUC10) for Palbociclib

498.3 nanograms*hour per milliliter (ng*hr/mL) Geometric Coefficient of Variation 28

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, and 24 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

AUC24 is AUCtau, where the dosing interval (tau) is 24 hours. AUC24 in the single-dose part (lead-in phase) for palbociclib was obtained by linear/log trapezoidal method.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: AUC From Time 0 to the Time 24 Hours (AUC24) for Palbociclib

1217 ng*hr/mL Geometric Coefficient of Variation 22

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

AUClast for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Palbociclib

2308 ng*hr/mL Geometric Coefficient of Variation 27

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

AUCinf for palbociclib in the single-dose part (lead-in phase) was calculated as AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel was the rate constant for terminal phase obtained by linear regression of the log-linear concentration-time curve.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Palbociclib

2386 ng*hr/mL Geometric Coefficient of Variation 27

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

Kel for palbociclib in the single-dose part (lead-in phase) was obtained by linear regression of the log-linear concentration-time curve.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: Rate Constant for Terminal Phase (Kel) for Palbociclib

0.03006 per hour Standard Deviation 0.00420

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

MRT for palbociclib in the single-dose part (lead-in phase) was calculated as AUMCinf/AUCinf, where AUMCinf was area under the first moment curve from time 0 to infinity.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: Mean Residence Time (MRT) for Palbociclib

34.42 hours Standard Deviation 4.32

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

t1/2 for palbociclib in the single-dose part (lead-in phase) was calculated as Loge(2)/kel.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: Terminal Half-Life (t1/2) for Palbociclib

23.46 hours Standard Deviation 3.14

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

CL/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/AUCinf.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: Apparent Oral Clearance (CL/F) for Palbociclib

52.40 liters per hour (L/hr) Geometric Coefficient of Variation 27

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose part.

Vz/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/(AUCinf * kel).

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Single-dose PK: Apparent Volume of Distribution (Vz/F) for Palbociclib

1758 liters Geometric Coefficient of Variation 21

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the multiple-dose part.

Css,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: Maximum Plasma Concentration at Steady State (Css,Max) for Palbociclib

139.7 ng/mL Geometric Coefficient of Variation 28

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the multiple-dose part.

Css,min of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: Minimum Plasma Concentration at Steady State (Css,Min) for Palbociclib

67.55 ng/mL Geometric Coefficient of Variation 46

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the multiple-dose part.

AUCss,tau of palbociclib in the multiple-dose part (Cycle 1) was determined by linear/log trapezoidal method.

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: AUC Within a Dosing Interval of Tau (=24 Hours) at Steady State (AUCss,Tau) for Palbociclib

2501 ng*hr/mL Geometric Coefficient of Variation 29

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the multiple-dose part.

Css,av of palbociclib in the multiple-dose part (Cycle 1) was calculated as AUCss,tau/tau, where tau was 24 hours.

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: Average Plasma Concentration at Steady State (Css,av) for Palbociclib

104.2 ng/mL Geometric Coefficient of Variation 29

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the multiple-dose part.

Tss,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data as time of first occurrence within tau (=24 hours) at steady state.

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for Palbociclib

6.05 hours Interval 3.97 to 10.0

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest and a well characterized terminal phase in the multiple-dose part.

Vz/F of palbociclib in the multiple-dose part (Cycle 1) was calculated as Dose/(AUCss,tau * kel), where AUCss,tau was the AUC within a dosing interval of tau (=24 hours) at steady state and kel was the terminal phase rate constant following multiple-dose calculated by a linear regression of the log-linear concentration-time curve.

Outcome measures

Measure

Palbociclib + Letrozole n=23 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: Vz/F for Palbociclib

1910 Liters Geometric Coefficient of Variation 29

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest and a well characterized terminal phase in the multiple-dose part .

t1/2 of palbociclib in the multiple-dose part (Cycle 1) was calculated as ln (2)/kel, where kel was the terminal phase rate constant following multiple-dose calculated by a linear regression of the log-linear concentration-time curve.

Outcome measures

Measure

Palbociclib + Letrozole n=23 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: t1/2 for Palbociclib

27.26 hours Standard Deviation 3.19

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the multiple-dose part.

CL/F of palbociclib in the multiple-dose part (Cycle 1) was calculated as Dose/AUCss,tau, where AUCss,tau was the AUC within a dosing interval of tau (=24 hours) at steady state.

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: CL/F for Palbociclib

49.97 L/hr Geometric Coefficient of Variation 29

PRIMARY outcome

Timeframe: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the multiple-dose part.

PTF of palbociclib in the multiple-dose part (Cycle 1) was determined as (Css,max - Css,min)/Css,av. Css,max and Css,min were observed directly from data while Css,av was calculated as AUCss,tau/tau, where tau was 24 hours.

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Multiple-dose PK: Peak to Trough Fluctuation at Steady State (PTF) for Palbociclib

0.6652 ratio Geometric Coefficient of Variation 27

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, and 24 hours post dose; Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose and multiple-dose part.

Rac of palbociclib was determined as AUCss,tau/AUCsd,tau, where AUCss,tau (tau=24 hours) was from multiple-dose part (Cycle 1) and AUCsd,tau was AUC24 from single-dose part (lead-in phase).

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Observed Accumulation Ratio (Rac) for Palbociclib

2.042 ratio Geometric Coefficient of Variation 27

PRIMARY outcome

Timeframe: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose; Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24 hours post dose on Day 21

Population: All enrolled and treated participants who had at least 1 PK parameter of primary interest in the single-dose and multiple-dose part.

Rss of palbociclib was calculated as AUCss,tau/AUCinf, where AUCss,tau (tau=24 hours) was from multiple-dose part (Cycle 1) and AUCinf was from single-dose part (lead-in phase).

Outcome measures

Measure

Palbociclib + Letrozole n=24 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Steady State Accumulation Ratio (Rss) for Palbociclib

1.036 ratio Geometric Coefficient of Variation 26

SECONDARY outcome

Timeframe: From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity on or after the first dose of investigational product administration. AEs included both SAEs and non-serious AEs. Causality to study treatment was determined by the investigator.

Outcome measures

Measure	Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Treatment-emergent AEs (all causalities)	26 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Treatment-emergent AEs (treatment-related)	26 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Treatment-emergent SAEs (all causalities)	4 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Treatment-emergent SAEs (treatment-related)	1 Participants

SECONDARY outcome

Timeframe: From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity on or after the first dose of investigational product administration. AEs included both SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. AEs were graded by NCI CTCAE version 4.0: Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.

Outcome measures

Measure	Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade Grade 1	0 Participants
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade Grade 2	5 Participants
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade Grade 3	16 Participants
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade Grade 4	5 Participants
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade Grade 5	0 Participants

SECONDARY outcome

Timeframe: From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication.

The number of participants with the following laboratory test abnormalities meeting any of the Grades 1 to 4 criteria per the NCI CTCAE (version 4.0) is summarized: anemia, lymphopenia, neutropenia, platelet count decreased, white blood cell (WBC) decreased, alanine aminotransferase (ALT) increased, alkaline phosphatase increased, aspartate aminotransferase (AST) increased, bilirubin (total) increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, and hyponatremia. Grade 1=mild, Grade 2=moderate, Grade 3=severe and Grade 4=life-threatening. One participant might had more than 1 laboratory test abnormality.

Outcome measures

Measure	Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Number of Participants With Laboratory Test Abnormalities Platelet count decreased	20 Participants
Number of Participants With Laboratory Test Abnormalities Anemia	23 Participants
Number of Participants With Laboratory Test Abnormalities Lymphopenia	19 Participants
Number of Participants With Laboratory Test Abnormalities Neutropenia	26 Participants
Number of Participants With Laboratory Test Abnormalities WBC decreased	25 Participants
Number of Participants With Laboratory Test Abnormalities ALT increased	11 Participants
Number of Participants With Laboratory Test Abnormalities Alkaline phosphatase increased	12 Participants
Number of Participants With Laboratory Test Abnormalities AST increased	18 Participants
Number of Participants With Laboratory Test Abnormalities Bilirubin (total) increased	4 Participants
Number of Participants With Laboratory Test Abnormalities Creatinine increased	25 Participants
Number of Participants With Laboratory Test Abnormalities Hypercalcemia	1 Participants
Number of Participants With Laboratory Test Abnormalities Hyperglycemia	10 Participants
Number of Participants With Laboratory Test Abnormalities Hyperkalemia	0 Participants
Number of Participants With Laboratory Test Abnormalities Hypermagnesemia	2 Participants
Number of Participants With Laboratory Test Abnormalities Hypernatremia	6 Participants
Number of Participants With Laboratory Test Abnormalities Hypoalbuminemia	11 Participants
Number of Participants With Laboratory Test Abnormalities Hypocalcemia	11 Participants
Number of Participants With Laboratory Test Abnormalities Hypoglycemia	0 Participants
Number of Participants With Laboratory Test Abnormalities Hypokalemia	6 Participants
Number of Participants With Laboratory Test Abnormalities Hypomagnesemia	5 Participants
Number of Participants With Laboratory Test Abnormalities Hyponatremia	6 Participants

SECONDARY outcome

Timeframe: From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication.

QT interval (time from electrocardiogram [ECG] Q wave and the end of the T wave corresponding to electrical systole) corrected for heart rate using Fridericia's formula was QTcF and QT interval corrected for heart rate using Bazett's formula was QTcB. Categorical summarization criteria for QTcF and QTcB were as follows: 1) maximum absolute value of <450 milliseconds (msec), >=450 to <=480 msec, >=481 to <=500 msec, or >=500 msec; 2) maximum increase from baseline of <30 msec, >=30 to <60 msec, or >=60 msec. One participant could be reported under more than 1 categorical summarization criteria for QTcF and QTcB Parameters.

Outcome measures

Measure	Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcF >=481 to <=500 msec	1 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum increase in QTcF >=30 to <60 msec	9 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcF <450 msec	21 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcF >=450 to <=480 msec	4 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcF >500 msec	0 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum increase in QTcF <30 msec	17 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum increase in QTcF >=60 msec	0 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcB <450 msec	9 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcB >=450 to <=480 msec	16 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcB >=481 to <=500 msec	0 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum QTcB >500 msec	1 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum increase in QTcB <30 msec	16 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum increase in QTcB >=30 to <60 msec	9 Participants
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters Maximum increase in QTcB >=60 msec	1 Participants

SECONDARY outcome

Timeframe: From C1D1 to date of first documentation of PD or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure)

Population: Efficacy analysis set included all enrolled participants who started the treatment of Cycle 1.

PFS was defined as the time from Cycle 1 Day 1 (C1D1) to date of first documentation of disease progression (PD) or death due to any cause, whichever occurred first. Documentation of progression was by objective disease assessment as defined by the Response Evaluation Criteria in Solid Tumor (RECIST) (version 1.1). PD was defined as a >=20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 millimeter (mm); or unequivocal progression of pre-existing lesions for non-target disease; or appearance of new unequivocal malignant lesions. Median PFS was estimated using the Kaplan-Meier method.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Progression-Free Survival (PFS)

18.6 Months Interval 6.5 to 27.7

SECONDARY outcome

Timeframe: From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure)

Population: Efficacy analysis set included all enrolled participants who started the treatment of Cycle 1.

ORR was the percentage of participants with an objective response (complete response [CR] or partial response [PR]). Per RECIST (version 1.1). CR: complete disappearance of all target lesions except nodal disease or disappearance of all non-target lesions and normalization of tumor marker levels. All target nodes/lymph nodes must decrease to normal size (<10 mm short axis); PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions (short diameter=sum for target nodes; longest diameter=sum for all other target lesions). PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of new unequivocal malignant lesions.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Percentage of Participants Achieving Objective Response (Objective Response Rate [ORR])

19.2 Percentage of participants Interval 6.6 to 39.4

SECONDARY outcome

Timeframe: From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure)

Population: Efficacy analysis set included all enrolled participants who started the treatment of Cycle 1.

Disease control (DC) = CR, PR or stable disease (SD) >= 24 weeks according to RECIST version 1.1 recorded from C1D1 until disease progression or death due to any cause. CR: complete disappearance of all target lesions except nodal disease or disappearance of all non-target lesions and normalization of tumor marker levels. All target nodes/lymph nodes must decrease to normal size (<10 mm short axis); PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions (short diameter=sum for target nodes; longest diameter=sum for all other target lesions). SD: Does not qualify for CR, PR or progression. PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or appearance of new unequivocal malignant lesions.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR])

65.4 Percentage of participants Interval 44.3 to 82.8

SECONDARY outcome

Timeframe: From first documentation of CR or PR to date of first documentation of objective progression or death, whichever occurred first (up to maximum of 471 weeks of treatment exposure)

Population: Efficacy analysis set included all enrolled participants who started the treatment of Cycle 1. Here, 'Overall Number of Participants Analyzed' signifies participants in the efficacy analysis set who achieved an objective response.

Duration of response was the time from first documentation of CR or PR to date of first documentation of PD or death for the participants with an objective response (CR or PR). Per RECIST (version 1.1). CR: complete disappearance of all target lesions except nodal disease or disappearance of all non-target lesions and normalization of tumor marker levels. All target nodes/lymph nodes must decrease to normal size (<10 mm short axis); PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions (short diameter=sum for target nodes; longest diameter=sum for all other target lesions). PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of new unequivocal malignant lesions. Kaplan-Meier method was used.

Outcome measures

Measure

Palbociclib + Letrozole n=5 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

Duration of Response

25.1 Months Interval 8.3 to The upper limit of 95% confidence interval (CI) was not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: 1 year

Population: Efficacy analysis set included all enrolled participants who started the treatment of Cycle 1.

PFS was defined as the time from C1D1 to date of first documentation of PD or death due to any cause, whichever occurred first. Documentation of progression was by objective disease assessment as defined by the RECIST (version 1.1). PD was defined as a >=20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum was observed during therapy), with a minimum absolute increase of 5 millimeter (mm); or unequivocal progression of pre-existing lesions for non-target disease; or appearance of new unequivocal malignant lesions. One-year PFS probability was defined as the probability (expressed as percentage) of PFS at 1 year after C1D1. PFS probability was determined using the Kaplan-Meier method.

Outcome measures

Measure

Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.

1-Year PFS Probability

57.5 Percentage probability Interval 35.3 to 74.5

SECONDARY outcome

Timeframe: pre-dose of Cycle 1 Days 19, 20, 21 and Cycle 2 Day 1

Population: "Number of Participants Analyzed" represents all enrolled and treated participants who had letrozole concentration data. "Number Analyzed" represents the number of such participants who had data at each specified time point.

Plasma samples were analyzed for letrozole concentrations using a validated, sensitive and specific high-performance liquid chromatography tandem mass spectrometric (HPLC/MS/MS) method.

Outcome measures

Measure	Palbociclib + Letrozole n=25 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Trough Plasma Concentration of Letrozole Cycle 1 Day 19 pre-dose	83.70 nanograms per milliliter (ng/mL) Interval 30.8 to 134.0
Trough Plasma Concentration of Letrozole Cycle 1 Day 21 pre-dose	85.30 nanograms per milliliter (ng/mL) Interval 38.2 to 134.0
Trough Plasma Concentration of Letrozole Cycle 1 Day 20 pre-dose	83.85 nanograms per milliliter (ng/mL) Interval 41.4 to 141.0
Trough Plasma Concentration of Letrozole Cycle 2 Day 1 pre-dose	97.40 nanograms per milliliter (ng/mL) Interval 48.8 to 282.0

SECONDARY outcome

Timeframe: Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26

Population: All enrolled and treated participants who had both pre-dose value and at least 1 post dose value for at least 1 biomarker. "Number Analyzed" refers to the number of evaluable participants for each specified time point.

The pRb was one of the skin biomarkers and samples were assayed using immunohistochemistry (IHC) method. Ratio over baseline was calculated by dividing the H-score value for pRb at each specified time point by baseline value. The H-score value, which could range from 0 to 300 (strongest expression) with higher score representing stronger expression, was calculated from the total of each individual intensity of staining (0 [negative], 1+ [weak], 2+ [moderate], 3+ [strong]) multiplied by the percentages of cells (0 to 100) that represented that staining.

Outcome measures

Measure	Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Lead-in phase Day 2	0.523 ratio Geometric Coefficient of Variation 92.28
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Lead-in phase Day 1	0.644 ratio Geometric Coefficient of Variation 56.34
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Cycle 1 Day 21	0.535 ratio Geometric Coefficient of Variation 108.77
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Cycle 1 Day 22	0.773 ratio Geometric Coefficient of Variation 57.77
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Cycle 1 Day 23	0.799 ratio Geometric Coefficient of Variation 91.59
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Cycle 1 Day 24	1.493 ratio Geometric Coefficient of Variation 103.46
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Cycle 1 Day 25	1.165 ratio Geometric Coefficient of Variation 99.39
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression Cycle 1 Day 26	2.164 ratio Geometric Coefficient of Variation 87.80

SECONDARY outcome

Timeframe: Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26

Population: All enrolled and treated participants who had both pre-dose value and at least 1 post dose value for at least 1 biomarker. "Number Analyzed" refers to the number of evaluable participants for each specified time point.

The Ki67 was one of the skin biomarkers and samples were assayed using IHC method. Ratio over baseline was calculated by dividing the percentage of Ki67 positive cells at each specified time point by baseline value.

Outcome measures

Measure	Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Ratio Over Baseline for Skin Biomarker Ki67 Expression Cycle 1 Day 26	1.301 ratio Geometric Coefficient of Variation 61.26
Ratio Over Baseline for Skin Biomarker Ki67 Expression Lead-in phase Day 1	0.985 ratio Geometric Coefficient of Variation 42.32
Ratio Over Baseline for Skin Biomarker Ki67 Expression Lead-in phase Day 2	0.868 ratio Geometric Coefficient of Variation 64.99
Ratio Over Baseline for Skin Biomarker Ki67 Expression Cycle 1 Day 21	0.495 ratio Geometric Coefficient of Variation 107.24
Ratio Over Baseline for Skin Biomarker Ki67 Expression Cycle 1 Day 22	0.408 ratio Geometric Coefficient of Variation 135.34
Ratio Over Baseline for Skin Biomarker Ki67 Expression Cycle 1 Day 23	0.599 ratio Geometric Coefficient of Variation 80.00
Ratio Over Baseline for Skin Biomarker Ki67 Expression Cycle 1 Day 24	0.832 ratio Geometric Coefficient of Variation 42.34
Ratio Over Baseline for Skin Biomarker Ki67 Expression Cycle 1 Day 25	0.920 ratio Geometric Coefficient of Variation 85.52

SECONDARY outcome

Timeframe: Baseline (Day -1 pre-dose), lead-in phase Day 1 (4, 8, 10, 24, 72, 120 hours post dose), Cycle 1 Day 21 (4, 8, 10, 24, 72, 96, 120 hours post dose), Cycle 2 Day 1 pre-dose

Population: All enrolled and treated participants who had both pre-dose value and at least 1 post dose value for at least 1 biomarker. "Number Analyzed" refers to the number of evaluable participants for each specified time point.

Blood samples were collected to provide serum for the assessments of TK activity. The concentrations of TK were determined using enzyme-linked immunosorbent assay (ELISA) method. Ratio of serum TK concentration at each specified time point over baseline value was presented.

Outcome measures

Measure	Palbociclib + Letrozole n=26 Participants Participants received a single dose of palbociclib 125 mg orally on Day 1 during the 5-day lead-in phase and received once QD from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Lead-in phase Day 1, 24 hours post dose	0.702 ratio Geometric Coefficient of Variation 48.93
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Lead-in phase Day 1, 72 hours post dose	0.530 ratio Geometric Coefficient of Variation 50.14
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 24 hours post dose	0.247 ratio Geometric Coefficient of Variation 164.37
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Lead-in phase Day 1, 4 hours post dose	0.780 ratio Geometric Coefficient of Variation 44.69
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Lead-in phase Day 1, 8 hours post dose	0.774 ratio Geometric Coefficient of Variation 43.65
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Lead-in phase Day 1, 10 hours post dose	0.733 ratio Geometric Coefficient of Variation 49.67
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Lead-in phase Day 1, 120 hours post dose	0.598 ratio Geometric Coefficient of Variation 74.40
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 4 hours post dose	0.260 ratio Geometric Coefficient of Variation 172.41
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 8 hours post dose	0.236 ratio Geometric Coefficient of Variation 191.22
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 10 hours post dose	0.236 ratio Geometric Coefficient of Variation 187.02
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 48 hours post dose	0.244 ratio Geometric Coefficient of Variation 166.61
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 72 hours post dose	0.268 ratio Geometric Coefficient of Variation 163.67
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 96 hours post dose	0.292 ratio Geometric Coefficient of Variation 176.92
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 1 Day 21, 120 hours post dose	0.455 ratio Geometric Coefficient of Variation 334.32
Ratio Over Baseline for Thymidine Kinase (TK) Concentration Cycle 2 Day 1, pre-dose	1.069 ratio Geometric Coefficient of Variation 248.43

Adverse Events

Palbociclib + Letrozole

Serious events: 4 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Measure	Palbociclib + Letrozole n=26 participants at risk Participants received a single dose of palbociclib 125 milligrams (mg) orally on Day 1 during the 5-day lead-in phase and received orally once daily (QD) from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Hepatobiliary disorders Drug-induced liver injury	3.8% 1/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Pneumonia	3.8% 1/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Abscess	3.8% 1/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Osteomyelitis	3.8% 1/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Pneumonia viral	3.8% 1/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.

Other adverse events

Measure	Palbociclib + Letrozole n=26 participants at risk Participants received a single dose of palbociclib 125 milligrams (mg) orally on Day 1 during the 5-day lead-in phase and received orally once daily (QD) from Day 1 to Day 21 (followed by 7 days off-treatment) during each 28-day treatment cycle. A treatment cycle was defined as 28 days in duration and Cycle 1 started on Day 6 of lead-in phase as Cycle 1 Day 1. Letrozole 2.5 mg was administered orally QD from Days 1 to 5 during the 5-day lead-in phase and from Days 1 to 28 during each 28-day treatment cycle.
Blood and lymphatic system disorders Anaemia	50.0% 13/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Leukopenia	42.3% 11/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Neutropenia	38.5% 10/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Blood and lymphatic system disorders Thrombocytopenia	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Cardiac disorders Sinus tachycardia	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Eye disorders Lenticular opacities	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Abdominal discomfort	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Constipation	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Diarrhoea	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Gingival pain	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Gingival ulceration	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Mouth ulceration	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Gastrointestinal disorders Toothache	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
General disorders Fatigue	19.2% 5/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
General disorders Pyrexia	19.2% 5/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Nasopharyngitis	19.2% 5/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Infections and infestations Upper respiratory tract infection	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Alanine aminotransferase increased	38.5% 10/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Aspartate aminotransferase increased	42.3% 11/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Blood alkaline phosphatase increased	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Blood bilirubin increased	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Blood cholesterol increased	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Blood creatinine increased	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Blood glucose increased	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Blood insulin increased	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Blood triglycerides increased	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Gamma-glutamyltransferase increased	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Haemoglobin decreased	23.1% 6/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Low density lipoprotein increased	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Neutrophil count decreased	61.5% 16/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Platelet count decreased	57.7% 15/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Red blood cell count decreased	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Weight decreased	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations Weight increased	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Investigations White blood cell count decreased	57.7% 15/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Decreased appetite	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Diabetes mellitus	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hypercholesterolaemia	19.2% 5/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hyperglycaemia	19.2% 5/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hyperlipidaemia	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hypertriglyceridaemia	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hyperuricaemia	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hypocalcaemia	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hypokalaemia	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Metabolism and nutrition disorders Hypophosphataemia	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	19.2% 5/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Bone pain	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Joint stiffness	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Nervous system disorders Dizziness	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Psychiatric disorders Insomnia	15.4% 4/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Respiratory, thoracic and mediastinal disorders Haemoptysis	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Respiratory, thoracic and mediastinal disorders Pneumonitis	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Skin and subcutaneous tissue disorders Alopecia	7.7% 2/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Skin and subcutaneous tissue disorders Pruritus	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.
Skin and subcutaneous tissue disorders Rash	11.5% 3/26 • From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks) The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another participant, or 1 participant may have experienced both a serious and non-serious event during the study.

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer Inc.

Phone: 1-800-718-1021

Email: ClinicalTrials.gov_Inquiries@pfizer.com

Results disclosure agreements

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

Restriction type: OTHER