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

• Sponsor: Pfizer (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02499146
• Collaborator: (none)
• Enrollment: 26
• Locations: 7
• Arm: 1
• Anticipated Duration (Months): 88.6
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Breast Cancer	Drug: Palbociclib; Drug: Letrozole	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: 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
• Actual Study Start Date: Sep 11, 2015
• Actual Primary Completion Date: Jul 31, 2018
• Anticipated Study Completion Date: Jan 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Combination therapy of palbociclib and letrozole	Drug: Palbociclib; 125 mg orally once daily with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle; Drug: Letrozole; 2.5 mg , orally once daily (continuously)

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

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

8. 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.

9. 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.

10. 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.

11. 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).

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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).

22. 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 calcualted 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 Outcome Measures

1. 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 (up to 2.8 years by primary completion date of 31 July 2018)]

   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.

2. Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade [up to 2.8 years by primary completion date of 31 July 2018]

   Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. 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.

3. Number of Participants With Laboratory Test Abnormalities [up to 2.8 years by primary completion date of 31 July 2018]

   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) was 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.

4. Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters [up to 2.8 years by primary completion date of 31 July 2018]

   QT interval (time from electrocardiogram [ECG] Q wave to 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 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.

5. Progression-Free Survival (PFS) [Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018]

   PFS was defined as the time from Cycle 1 Day 1 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). Objective status of 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 mm; or unequivocal progression of pre-existing lesions for non-target disease; or appearance of new lesions.

6. Percentage of Participants Achieving Objective Response (Objective Response Rate [ORR]) [Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018]

   ORR was the percentage of participants with an objective response (complete response [CR] or partial response [PR]). Per RECIST (version 1.1), objective status of CR: target lesions and non-target diseases achieved CR, without new lesions; objective status of PR: target lesions achieved CR or PR while non-target diseases were non-CR/non-PD, indeterminate or missing, and without new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target diseases, CR: disappearance of all non-target lesions and normalization of tumor marker levels; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits; Indeterminate: progression had not been determined and >=1 non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.

7. Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR]) [Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018]

   DCR was the percentage of participants achieving disease control (CR, PR or stable disease [SD] >=24 weeks from Cycle 1 Day 1 to PD or death due to any cause). The definitions for objective status of CR, PR, and PD per RECIST (version 1.1) can be found in the previous Outcome Measures. Per RECIST (version 1.1), objective status of SD: target lesions achieved SD (i.e., did not qualify for CR, PR or PD) while non-target diseases were assessed as non-CR/non-PD, indeterminate or missing, and there were no new lesions.

8. Duration of Response [Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018]

   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). The definitions of CR, PR, and PD per RECIST (version 1.1) can be found in the previous Outcome Measures.

9. 1-Year PFS Probability [1 year]

   One-year PFS probability was defined as the probability (expressed as percentage) of PFS at 1 year after Cycle 1 Day 1.

10. 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.

11. 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.

12. 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.

13. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

1. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beijing Cancer Hospital/Oncology department	Beijing	Beijing	China	100142
2	Sun Yat-Sen University Cancer Center	Guangzhou	Guangdong	China	510060
3	Guangdong General Hospital/Department of Breast Surgery	Guangzhou	Guangdong	China	510080
4	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang	China	150081
5	The first hospital of jilin university	Changchun	Jilin	China	130021
6	The First Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China	310003
7	Cancer Institute and Hospital, Chinese Academy of Medical Sciences	Beijing		China	100021

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Jul 24, 2015
• Statistical Analysis Plan - May 16, 2016

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02499146
• Other Study ID Numbers: A5481019
• First Posted: Jul 15, 2015
• Last Update Posted: Jul 12, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Pfizer: Palbociclib; PD-0332991; pharmacokinetics; breast cancer patients; Chinese
• Additional relevant MeSH terms: Breast Neoplasms; Letrozole; Palbociclib

Study Results

Participant Flow

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Period Title: Overall Study
STARTED	26
COMPLETED	0
NOT COMPLETED	26

Baseline Characteristics

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Overall Participants	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.8 (7.6)
Sex: Female, Male (Count of Participants)
Female	26 100%
Male	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	26 100%

Outcome Measures

1. Primary Outcome

Title	Single-dose Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) for Palbociclib
Description	Cmax of palbociclib in the single-dose part (lead-in phase) was observed directly from data.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [nanograms per milliliter (ng/mL)]	82.14 (25)

2. Primary Outcome

Title	Single-dose PK: Time to Reach Maximum Plasma Concentration (Tmax) for Palbociclib
Description	Tmax for palbociclib in the single-dose part (lead-in phase) was observed directly from data as time of first occurrence.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Median (Full Range) [hours]	7.94

3. Primary Outcome

Title	Single-dose PK: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to the Time 10 Hours (AUC10) for Palbociclib
Description	AUC10 for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, and 10 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [nanograms*hour per milliliter (ng*hr/mL)]	498.3 (28)

4. Primary Outcome

Title	Single-dose PK: AUC From Time 0 to the Time 24 Hours (AUC24) for Palbociclib
Description	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.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, and 24 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	1217 (22)

5. Primary Outcome

Title	Single-dose PK: AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Palbociclib
Description	AUClast for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	2308 (27)

6. Primary Outcome

Title	Single-dose PK: AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Palbociclib
Description	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.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	2386 (27)

7. Primary Outcome

Title	Single-dose PK: Rate Constant for Terminal Phase (Kel) for Palbociclib
Description	Kel for palbociclibo in the single-dose part (lead-in phase) was obtained by linear regression of the log-linear concentration-time curve.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Mean (Standard Deviation) [per hour]	0.03006 (0.00420)

8. Primary Outcome

Title	Single-dose PK: Mean Residence Time (MRT) for Palbociclib
Description	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.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Mean (Standard Deviation) [hours]	34.42 (4.32)

9. Primary Outcome

Title	Single-dose PK: Terminal Half-Life (t1/2) for Palbociclib
Description	t1/2 for palbociclib in the single-dose part (lead-in phase) was calculated as Loge(2)/kel.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Mean (Standard Deviation) [hours]	23.46 (3.14)

10. Primary Outcome

Title	Single-dose PK: Apparent Oral Clearance (CL/F) for Palbociclib
Description	CL/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/AUCinf.
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [liters per hour (L/hr)]	52.40 (27)

11. Primary Outcome

Title	Single-dose PK: Apparent Volume of Distribution (Vz/F) for Palbociclib
Description	Vz/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/(AUCinf * kel).
Time Frame	Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Geometric Mean (Geometric Coefficient of Variation) [liters]	1758 (21)

12. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	139.7 (28)

13. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	67.55 (46)

14. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [ng*hr/mL]	2501 (29)

15. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	104.2 (29)

16. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Median (Full Range) [hours]	6.05

17. Primary Outcome

Title	Multiple-dose PK: Vz/F for Palbociclib
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	23
Geometric Mean (Geometric Coefficient of Variation) [Liters]	1910 (29)

18. Primary Outcome

Title	Multiple-dose PK: t1/2 for Palbociclib
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	23
Mean (Standard Deviation) [hours]	27.26 (3.19)

19. Primary Outcome

Title	Multiple-dose PK: CL/F for Palbociclib
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [L/hr]	49.97 (29)

20. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [ratio]	0.6652 (27)

21. Primary Outcome

Title	Observed Accumulation Ratio (Rac) for Palbociclib
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [ratio]	2.042 (27)

22. Primary Outcome

Title	Steady State Accumulation Ratio (Rss) for Palbociclib
Description	Rss of palbociclib was calcualted 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).
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	24
Geometric Mean (Geometric Coefficient of Variation) [ratio]	1.036 (26)

23. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	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.
Time Frame	From first dose of study medication up to 28 days after last dose (up to 2.8 years by primary completion date of 31 July 2018)

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study medication.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Treatment-emergent AEs (all causalities)	26 100%
Treatment-emergent AEs (treatment-related)	26 100%
Treatment-emergent SAEs (all causalities)	2 7.7%
Treatment-emergent SAEs (treatment-related)	1 3.8%

24. Secondary Outcome

Title	Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade
Description	Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of study treatment. 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.
Time Frame	up to 2.8 years by primary completion date of 31 July 2018

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study medication.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Grade 1	0 0%
Grade 2	5 19.2%
Grade 3	17 65.4%
Grade 4	4 15.4%
Grade 5	0 0%

25. Secondary Outcome

Title	Number of Participants With Laboratory Test Abnormalities
Description	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) was 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.
Time Frame	up to 2.8 years by primary completion date of 31 July 2018

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study medication.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Anemia	22 84.6%
Lymphopenia	19 73.1%
Neutropenia	26 100%
Platelet count decreased	19 73.1%
WBC decreased	25 96.2%
ALT increased	8 30.8%
Alkaline phosphatase increased	12 46.2%
AST increased	16 61.5%
Bilirubin (total) increased	3 11.5%
Creatinine increased	25 96.2%
Hypercalcemia	0 0%
Hyperglycemia	10 38.5%
Hyperkalemia	0 0%
Hypermagnesemia	2 7.7%
Hypernatremia	6 23.1%
Hypoalbuminemia	11 42.3%
Hypocalcemia	11 42.3%
Hypoglycemia	0 0%
Hypokalemia	6 23.1%
Hypomagnesemia	5 19.2%
Hyponatremia	5 19.2%

26. Secondary Outcome

Title	Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters
Description	QT interval (time from electrocardiogram [ECG] Q wave to 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 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.
Time Frame	up to 2.8 years by primary completion date of 31 July 2018

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study medication.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Maximum QTcF <450 msec	21 80.8%
Maximum QTcF >=450 to <=480 msec	4 15.4%
Maximum QTcF >=481 to <=500 msec	1 3.8%
Maximum QTcF >500 msec	0 0%
Maximum increase in QTcF <30 msec	17 65.4%
Maximum increase in QTcF >=30 to <60 msec	9 34.6%
Maximum increase in QTcF >=60 msec	0 0%
Maximum QTcB <450 msec	10 38.5%
Maximum QTcB >=450 to <=480 msec	15 57.7%
Maximum QTcB >500 msec	1 3.8%
Maximum QTcB >=481 to <=500 msec	0 0%
Maximum increase in QTcB <30 msec	16 61.5%
Maximum increase in QTcB >=30 to <60 msec	9 34.6%
Maximum increase in QTcB >=60 msec	1 3.8%

27. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as the time from Cycle 1 Day 1 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). Objective status of 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 mm; or unequivocal progression of pre-existing lesions for non-target disease; or appearance of new lesions.
Time Frame	Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018

Outcome Measure Data

Analysis Population Description

All enrolled participants who started the treatment of Cycle 1.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Median (95% Confidence Interval) [months]	18.6

28. Secondary Outcome

Title	Percentage of Participants Achieving Objective Response (Objective Response Rate [ORR])
Description	ORR was the percentage of participants with an objective response (complete response [CR] or partial response [PR]). Per RECIST (version 1.1), objective status of CR: target lesions and non-target diseases achieved CR, without new lesions; objective status of PR: target lesions achieved CR or PR while non-target diseases were non-CR/non-PD, indeterminate or missing, and without new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target diseases, CR: disappearance of all non-target lesions and normalization of tumor marker levels; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits; Indeterminate: progression had not been determined and >=1 non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.
Time Frame	Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018

Outcome Measure Data

Analysis Population Description

All enrolled participants who started the treatment of Cycle 1.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Number (95% Confidence Interval) [percentage of participants]	19.2 73.8%

29. Secondary Outcome

Title	Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR])
Description	DCR was the percentage of participants achieving disease control (CR, PR or stable disease [SD] >=24 weeks from Cycle 1 Day 1 to PD or death due to any cause). The definitions for objective status of CR, PR, and PD per RECIST (version 1.1) can be found in the previous Outcome Measures. Per RECIST (version 1.1), objective status of SD: target lesions achieved SD (i.e., did not qualify for CR, PR or PD) while non-target diseases were assessed as non-CR/non-PD, indeterminate or missing, and there were no new lesions.
Time Frame	Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018

Outcome Measure Data

Analysis Population Description

All enrolled participants who started the treatment of Cycle 1.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Number (95% Confidence Interval) [percentage of participants]	65.4 251.5%

30. Secondary Outcome

Title	Duration of Response
Description	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). The definitions of CR, PR, and PD per RECIST (version 1.1) can be found in the previous Outcome Measures.
Time Frame	Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018

Outcome Measure Data

Analysis Population Description

All enrolled participants who started the treatment of Cycle 1 and achieved an objective response (CR or PR per RECIST version 1.1).

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	5
Median (95% Confidence Interval) [months]	25.1

31. Secondary Outcome

Title	1-Year PFS Probability
Description	One-year PFS probability was defined as the probability (expressed as percentage) of PFS at 1 year after Cycle 1 Day 1.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

All enrolled participants who started the treatment of Cycle 1.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Number (95% Confidence Interval) [percentage of PFS]	57.5

32. Secondary Outcome

Title	Trough Plasma Concentration of Letrozole
Description	Plasma samples were analyzed for letrozole concentrations using a validated, sensitive and specific high-performance liquid chromatography tandem mass spectrometric (HPLC/MS/MS) method.
Time Frame	pre-dose of Cycle 1 Days 19, 20, 21 and Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

"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.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	25
Cycle 1 Day 19 pre-dose	83.70
Cycle 1 Day 20 pre-dose	83.85
Cycle 1 Day 21 pre-dose	85.30
Cycle 2 Day 1 pre-dose	97.40

33. Secondary Outcome

Title	Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression
Description	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.
Time Frame	Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Lead-in phase Day 1	0.644 (56.34)
Lead-in phase Day 2	0.523 (92.28)
Cycle 1 Day 21	0.535 (108.77)
Cycle 1 Day 22	0.773 (57.77)
Cycle 1 Day 23	0.799 (91.59)
Cycle 1 Day 24	1.493 (103.46)
Cycle 1 Day 25	1.165 (99.39)
Cycle 1 Day 26	2.164 (87.80)

34. Secondary Outcome

Title	Ratio Over Baseline for Skin Biomarker Ki67 Expression
Description	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.
Time Frame	Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Lead-in phase Day 1	0.985 (42.32)
Lead-in phase Day 2	0.868 (64.99)
Cycle 1 Day 21	0.495 (107.24)
Cycle 1 Day 22	0.408 (135.34)
Cycle 1 Day 23	0.599 (80.00)
Cycle 1 Day 24	0.832 (42.34)
Cycle 1 Day 25	0.920 (85.52)
Cycle 1 Day 26	1.301 (61.26)

35. Secondary Outcome

Title	Ratio Over Baseline for Thymidine Kinase (TK) Concentration
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
Measure Participants	26
Lead-in phase Day 1, 4 hours post dose	0.780 (44.69)
Lead-in phase Day 1, 8 hours post dose	0.774 (43.65)
Lead-in phase Day 1, 10 hours post dose	0.733 (49.67)
Lead-in phase Day 1, 24 hours post dose	0.702 (48.93)
Lead-in phase Day 1, 72 hours post dose	0.530 (50.14)
Lead-in phase Day 1, 120 hours post dose	0.598 (74.40)
Cycle 1 Day 21, 4 hours post dose	0.260 (172.41)
Cycle 1 Day 21, 8 hours post dose	0.236 (191.22)
Cycle 1 Day 21, 10 hours post dose	0.236 (187.02)
Cycle 1 Day 21, 24 hours post dose	0.247 (164.37)
Cycle 1 Day 21, 48 hours post dose	0.244 (166.61)
Cycle 1 Day 21, 72 hours post dose	0.268 (163.67)
Cycle 1 Day 21, 96 hours post dose	0.292 (176.92)
Cycle 1 Day 21, 120 hours post dose	0.455 (334.32)
Cycle 2 Day 1, pre-dose	1.069 (248.43)

Adverse Events

Time Frame	From first dose of study treatment up to 28 days after last dose (up to 2.8 years by primary completion date of 31 July 2018)
Adverse Event Reporting Description	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.
Arm/Group Title	Palbociclib + Letrozole
Arm/Group Description	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.
All Cause Mortality
	Palbociclib + Letrozole
	Affected / at Risk (%)	# Events
Total	0/26 (0%)
Serious Adverse Events
	Palbociclib + Letrozole
	Affected / at Risk (%)	# Events
Total	2/26 (7.7%)
Hepatobiliary disorders
Drug-induced liver injury	1/26 (3.8%)
Infections and infestations
Pneumonia	1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	Palbociclib + Letrozole
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Anaemia	12/26 (46.2%)
Leukopenia	10/26 (38.5%)
Neutropenia	10/26 (38.5%)
Thrombocytopenia	2/26 (7.7%)
Eye disorders
Lenticular opacities	3/26 (11.5%)
Gastrointestinal disorders
Abdominal discomfort	3/26 (11.5%)
Diarrhoea	2/26 (7.7%)
Gingival pain	2/26 (7.7%)
Gingival ulceration	4/26 (15.4%)
Mouth ulceration	3/26 (11.5%)
Toothache	3/26 (11.5%)
General disorders
Fatigue	5/26 (19.2%)
Pyrexia	5/26 (19.2%)
Infections and infestations
Nasopharyngitis	5/26 (19.2%)
Upper respiratory tract infection	3/26 (11.5%)
Investigations
Alanine aminotransferase increased	7/26 (26.9%)
Aspartate aminotransferase increased	9/26 (34.6%)
Blood alkaline phosphatase increased	3/26 (11.5%)
Blood cholesterol increased	2/26 (7.7%)
Blood creatinine increased	2/26 (7.7%)
Blood glucose increased	3/26 (11.5%)
Blood insulin increased	2/26 (7.7%)
Blood triglycerides increased	3/26 (11.5%)
Gamma-glutamyltransferase increased	3/26 (11.5%)
Haemoglobin decreased	6/26 (23.1%)
Low density lipoprotein increased	2/26 (7.7%)
Neutrophil count decreased	16/26 (61.5%)
Platelet count decreased	14/26 (53.8%)
Red blood cell count decreased	3/26 (11.5%)
Weight decreased	2/26 (7.7%)
Weight increased	3/26 (11.5%)
White blood cell count decreased	15/26 (57.7%)
Metabolism and nutrition disorders
Decreased appetite	3/26 (11.5%)
Diabetes mellitus	2/26 (7.7%)
Hypercholesterolaemia	4/26 (15.4%)
Hyperglycaemia	3/26 (11.5%)
Hyperlipidaemia	2/26 (7.7%)
Hypertriglyceridaemia	2/26 (7.7%)
Hyperuricaemia	4/26 (15.4%)
Hypocalcaemia	4/26 (15.4%)
Hypokalaemia	4/26 (15.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/26 (11.5%)
Bone pain	2/26 (7.7%)
Joint stiffness	3/26 (11.5%)
Musculoskeletal pain	2/26 (7.7%)
Nervous system disorders
Dizziness	3/26 (11.5%)
Psychiatric disorders
Insomnia	4/26 (15.4%)
Respiratory, thoracic and mediastinal disorders
Cough	2/26 (7.7%)
Haemoptysis	2/26 (7.7%)
Pneumonitis	2/26 (7.7%)
Skin and subcutaneous tissue disorders
Alopecia	2/26 (7.7%)
Pruritus	2/26 (7.7%)
Rash	3/26 (11.5%)

Limitations/Caveats

The reported results were based on the data cut off at primary completion date (31 July 2018). The study is still ongoing and results will be updated after completion of the whole study.

More Information

Certain Agreements

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

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.