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

A PHASE 1 OPEN-LABEL PHARMACOKINETICS STUDY OF PALBOCICLIB, A CYCLIN-DEPENDENT KINASE 4 AND 6 (CDK4/6) INHIBITOR, IN POSTMENOPAUSAL CHINESE WOMEN WITH ER (+), HER2 (-) ADVANCED BREAST CANCER

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02499146

Enrollment

Registered

2015-07-15

Start date

2015-09-11

Completion date

2024-12-24

Last updated

2026-02-11

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Advanced Breast Cancer

Keywords

Palbociclib, PD-0332991, pharmacokinetics, breast cancer patients, Chinese

Brief summary

As part of the global clinical development program for Palbociclib, studies are planned in cancer patients in China. An assessment of Palbociclib pharmacokinetics in Chinese patients, as required by the Chinese Health Authorities, is therefore warranted. In addition, safety and efficacy will be also evaluated. The single and multiple 125 mg oral dose pharmacokinetics of Palbociclib will be characterized.

Interventions

DRUGPalbociclib

125 mg orally once daily with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle

DRUGLetrozole

2.5 mg , orally once daily (continuously)

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

* ER(+), HER2(-), postmenopausal adult (ages 18-65 years, inclusive) Chinese women with proven diagnosis of adenocarcinoma of the breast with evidence locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated. a. Postmenopausal women: i. Prior bilateral surgical oophorectomy; or ii. Medically confirmed post-menopausal status defined as spontaneous cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause b. Documentation of histologically or cytologically confirmed diagnosis of: i. ER(+) breast cancer. c. Documentation of HER2(-) breast cancer. d. Previously untreated with any systemic anti cancer therapy for their locoregionally recurrent or metastatic ER+ disease. * Measurable disease as defined per RECIST v.1.1 or bone-only disease. - Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented.

Exclusion criteria

* HER2-positive tumor as defined by documentation of erbB-2 gene amplification by FISH (as defined by a HER2/CEP17 ratio ≥2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer's kit instruction) or documentation of HER2 overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory results * Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions \[pleural, pericardial, peritoneal\], pulmonary lymphangitis, and over 50% liver involvement).

Design outcomes

Primary

Measure	Time frame	Description
Single-dose PK: Apparent Volume of Distribution (Vz/F) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	Vz/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/(AUCinf \* kel).
Single-dose Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	Cmax of palbociclib in the single-dose part (lead-in phase) was observed directly from data.
Single-dose PK: Time to Reach Maximum Plasma Concentration (Tmax) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	Tmax for palbociclib in the single-dose part (lead-in phase) was observed directly from data as time of first occurrence.
Single-dose PK: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to the Time 10 Hours (AUC10) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, and 10 hours post dose	AUC10 for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
Single-dose PK: AUC From Time 0 to the Time 24 Hours (AUC24) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, and 24 hours post dose	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.
Single-dose PK: AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	AUClast for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
Single-dose PK: AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	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.
Single-dose PK: Rate Constant for Terminal Phase (Kel) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	Kel for palbociclib in the single-dose part (lead-in phase) was obtained by linear regression of the log-linear concentration-time curve.
Single-dose PK: Mean Residence Time (MRT) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	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.
Single-dose PK: Terminal Half-Life (t1/2) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	t1/2 for palbociclib in the single-dose part (lead-in phase) was calculated as Loge(2)/kel.
Single-dose PK: Apparent Oral Clearance (CL/F) for Palbociclib	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose	CL/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/AUCinf.
Multiple-dose PK: Maximum Plasma Concentration at Steady State (Css,Max) for Palbociclib	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	Css,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
Multiple-dose PK: Minimum Plasma Concentration at Steady State (Css,Min) for Palbociclib	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	Css,min of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
Multiple-dose PK: AUC Within a Dosing Interval of Tau (=24 Hours) at Steady State (AUCss,Tau) for Palbociclib	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	AUCss,tau of palbociclib in the multiple-dose part (Cycle 1) was determined by linear/log trapezoidal method.
Multiple-dose PK: Average Plasma Concentration at Steady State (Css,av) for Palbociclib	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	Css,av of palbociclib in the multiple-dose part (Cycle 1) was calculated as AUCss,tau/tau, where tau was 24 hours.
Multiple-dose PK: Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for Palbociclib	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	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.
Multiple-dose PK: Vz/F for Palbociclib	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	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.
Multiple-dose PK: t1/2 for Palbociclib	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	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.
Multiple-dose PK: CL/F for Palbociclib	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	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.
Multiple-dose PK: Peak to Trough Fluctuation at Steady State (PTF) for Palbociclib	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	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.
Observed Accumulation Ratio (Rac) for Palbociclib	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	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).
Steady State Accumulation Ratio (Rss) for Palbociclib	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	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).

Secondary

Measure	Time frame	Description
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	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)	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.
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade	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)	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.
Number of Participants With Laboratory Test Abnormalities	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 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.
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters	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)	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.
Progression-Free Survival (PFS)	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)	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.
Percentage of Participants Achieving Objective Response (Objective Response Rate [ORR])	From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure)	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.
Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR])	From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure)	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.
Duration of Response	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)	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.
1-Year PFS Probability	1 year	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.
Trough Plasma Concentration of Letrozole	pre-dose of Cycle 1 Days 19, 20, 21 and Cycle 2 Day 1	Plasma samples were analyzed for letrozole concentrations using a validated, sensitive and specific high-performance liquid chromatography tandem mass spectrometric (HPLC/MS/MS) method.
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression	Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26	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.
Ratio Over Baseline for Skin Biomarker Ki67 Expression	Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26	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.
Ratio Over Baseline for Thymidine Kinase (TK) Concentration	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	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.

Countries

China

Contacts

STUDY_DIRECTORPfizer CT.gov Call Center

Pfizer

Participant flow

Participants by arm

Arm	Count
Palbociclib + Letrozole 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.	26
Total	26

Arm

Count

Palbociclib + Letrozole

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.

Total

Baseline characteristics

Characteristic	Palbociclib + Letrozole
Age, Continuous	50.8 years STANDARD_DEVIATION 7.6
Race/Ethnicity, Customized Asian	26 Participants
Sex: Female, Male Female	26 Participants
Sex: Female, Male Male	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 26
other Total, other adverse events	26 / 26
serious Total, serious adverse events	4 / 26

Outcome results

Primary

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

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

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	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

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

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

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	Multiple-dose PK: Average Plasma Concentration at Steady State (Css,av) for Palbociclib	104.2 ng/mL	Geometric Coefficient of Variation 29

Primary

Multiple-dose PK: CL/F for Palbociclib

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.

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	Multiple-dose PK: CL/F for Palbociclib	49.97 L/hr	Geometric Coefficient of Variation 29

Primary

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

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

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	Multiple-dose PK: Maximum Plasma Concentration at Steady State (Css,Max) for Palbociclib	139.7 ng/mL	Geometric Coefficient of Variation 28

Primary

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

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

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	Multiple-dose PK: Minimum Plasma Concentration at Steady State (Css,Min) for Palbociclib	67.55 ng/mL	Geometric Coefficient of Variation 46

Primary

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

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.

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	Multiple-dose PK: Peak to Trough Fluctuation at Steady State (PTF) for Palbociclib	0.6652 ratio	Geometric Coefficient of Variation 27

Primary

Multiple-dose PK: t1/2 for Palbociclib

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.

Time frame: 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 .

Arm	Measure	Value (MEAN)	Dispersion
Palbociclib + Letrozole	Multiple-dose PK: t1/2 for Palbociclib	27.26 hours	Standard Deviation 3.19

Primary

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

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.

Time frame: 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.

Arm	Measure	Value (MEDIAN)
Palbociclib + Letrozole	Multiple-dose PK: Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for Palbociclib	6.05 hours

Primary

Multiple-dose PK: Vz/F for Palbociclib

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.

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	Multiple-dose PK: Vz/F for Palbociclib	1910 Liters	Geometric Coefficient of Variation 29

Primary

Observed Accumulation Ratio (Rac) for Palbociclib

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).

Time frame: 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.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Palbociclib + Letrozole	Observed Accumulation Ratio (Rac) for Palbociclib	2.042 ratio	Geometric Coefficient of Variation 27

Primary