Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Letrozole

Palbociclib

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Protein Kinase Inhibitors

Combination therapy of palbociclib and letrozole

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)

Pfizer CT.gov Call Center

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.

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

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

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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

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

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

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.

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

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.

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

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.

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

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

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

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

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

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

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

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

Pfizer

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.

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.

Palbociclib + Letrozole

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

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

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.

Pfizer ClinicalTrials.gov Call Center

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

Multiple-dose PK: Vz/F for Palbociclib

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 .

Multiple-dose PK: t1/2 for Palbociclib

Multiple-dose PK: CL/F for Palbociclib

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

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

Observed Accumulation Ratio (Rac) for Palbociclib

Steady State Accumulation Ratio (Rss) for Palbociclib

Treatment-emergent AEs (all causalities)

Treatment-emergent AEs (treatment-related)

Treatment-emergent SAEs (all causalities)

Treatment-emergent SAEs (treatment-related)

Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade

Anemia

Lymphopenia

Neutropenia

Platelet count decreased

WBC decreased

ALT increased

Alkaline phosphatase increased

AST increased

Bilirubin (total) increased

Creatinine increased

Hypercalcemia

Hyperglycemia

Hyperkalemia

Hypermagnesemia

Hypernatremia

Hypoalbuminemia

Hypocalcemia

Hypoglycemia

Hypokalemia

Hypomagnesemia

Hyponatremia

Number of Participants With Laboratory Test Abnormalities

Maximum QTcF <450 msec

Maximum QTcF >=450 to <=480 msec

Maximum QTcF >=481 to <=500 msec

Maximum QTcF >500 msec

Maximum increase in QTcF <30 msec

Maximum increase in QTcF >=30 to <60 msec

Maximum increase in QTcF >=60 msec

Maximum QTcB <450 msec

Maximum QTcB >=450 to <=480 msec

Maximum QTcB >500 msec

Maximum QTcB >=481 to <=500 msec

Maximum increase in QTcB <30 msec

Maximum increase in QTcB >=30 to <60 msec

Maximum increase in QTcB >=60 msec

Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters

All enrolled participants who started the treatment of Cycle 1.

Progression-Free Survival (PFS)

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

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

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

Duration of Response

1-Year PFS Probability

Cycle 1 Day 19 pre-dose

Cycle 1 Day 20 pre-dose

Cycle 1 Day 21 pre-dose

Cycle 2 Day 1 pre-dose

"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.

Trough Plasma Concentration of Letrozole

Lead-in phase Day 1

Lead-in phase Day 2

Cycle 1 Day 21

Cycle 1 Day 22

Cycle 1 Day 23

Cycle 1 Day 24

Cycle 1 Day 25

Cycle 1 Day 26

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.

Spots Global Cancer Trial Database for Palbociclib Pharmacokinetics Study In Postmenopausal Chinese Women With ER (+), HER2 (-) Advanced Breast Cancer

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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