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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
26
125 mg orally once daily with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle
2.5 mg , orally once daily (continuously)
Beijing Cancer Hospital/Oncology department
Beijing, Beijing Municipality, China
Sun Yat-Sen University Cancer Center
Guangzhou, Guangdong, China
Guangdong General Hospital/Department of Breast Surgery
Guangzhou, Guangdong, China
Harbin Medical University Cancer Hospital
Harbin, Heilongjiang, China
Single-dose Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) for Palbociclib
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
Single-dose PK: Time to Reach Maximum Plasma Concentration (Tmax) for Palbociclib
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
Single-dose PK: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to the Time 10 Hours (AUC10) for Palbociclib
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
Single-dose PK: AUC From Time 0 to the Time 24 Hours (AUC24) for Palbociclib
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
Single-dose PK: AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Palbociclib
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
Single-dose PK: AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Palbociclib
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.
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The first hospital of jilin university
Changchun, Jilin, China
The First Affiliated Hospital of College of Medicine, Zhejiang University
Hangzhou, Zhejiang, China
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Beijing, China
Time frame: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
Single-dose PK: Rate Constant for Terminal Phase (Kel) for Palbociclib
Kel for palbociclib 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
Single-dose PK: Mean Residence Time (MRT) for Palbociclib
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
Single-dose PK: Terminal Half-Life (t1/2) for Palbociclib
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
Single-dose PK: Apparent Oral Clearance (CL/F) for Palbociclib
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
Single-dose PK: Apparent Volume of Distribution (Vz/F) for Palbociclib
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
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
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
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
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
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
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
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
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
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
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
Steady State Accumulation Ratio (Rss) for Palbociclib
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).
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
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
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 of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks)
Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade
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.
Time frame: 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)
Number of Participants With Laboratory Test Abnormalities
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.
Time frame: 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)
Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters
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.
Time frame: 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)
Progression-Free Survival (PFS)
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.
Time frame: 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)
Percentage of Participants Achieving Objective Response (Objective Response Rate [ORR])
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.
Time frame: From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure)
Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR])
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.
Time frame: From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure)
Duration of Response
Duration of response was the time from first documentation of CR or PR to date of first documentation of PD or death for the participants with an objective response (CR or PR). Per RECIST (version 1.1). CR: complete disappearance of all target lesions except nodal disease or disappearance of all non-target lesions and normalization of tumor marker levels. All target nodes/lymph nodes must decrease to normal size (\<10 mm short axis); PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions (short diameter=sum for target nodes; longest diameter=sum for all other target lesions). PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of new unequivocal malignant lesions. Kaplan-Meier method was used.
Time frame: 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)
1-Year PFS Probability
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.
Time frame: 1 year
Trough Plasma Concentration of Letrozole
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
Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression
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
Ratio Over Baseline for Skin Biomarker Ki67 Expression
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
Ratio Over Baseline for Thymidine Kinase (TK) Concentration
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