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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ER(+), HER2(-), postmenopausal adult (ages 18-65 years, inclusive) Chinese women with proven diagnosis of adenocarcinoma of the breast with evidence locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated. a. Postmenopausal women: i. Prior bilateral surgical oophorectomy; or ii. Medically confirmed post-menopausal status defined as spontaneous cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause b. Documentation of histologically or cytologically confirmed diagnosis of: i. ER(+) breast cancer. c. Documentation of HER2(-) breast cancer. d. Previously untreated with any systemic anti cancer therapy for their locoregionally recurrent or metastatic ER+ disease. Measurable disease as defined per RECIST v.1.1 or bone-only disease. - Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented. Exclusion Criteria: HER2-positive tumor as defined by documentation of erbB-2 gene amplification by FISH (as defined by a HER2/CEP17 ratio ≥2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer's kit instruction) or documentation of HER2 overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory results Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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 palbociclibo in the single-dose part (lead-in phase) was obtained by linear regression of the log-linear concentration-time curve. | 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. | 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. | 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. | 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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 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). | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade | 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. | up to 2.8 years by primary completion date of 31 July 2018 | 
| 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) 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. | up to 2.8 years by primary completion date of 31 July 2018 | 
| Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters | 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. | up to 2.8 years by primary completion date of 31 July 2018 | 
| Progression-Free Survival (PFS) | 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. | Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 | 
| 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), 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. | Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 | 
| Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR]) | 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. | Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 | 
| 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). The definitions of CR, PR, and PD per RECIST (version 1.1) can be found in the previous Outcome Measures. | Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 | 
| 1-Year PFS Probability | One-year PFS probability was defined as the probability (expressed as percentage) of PFS at 1 year after Cycle 1 Day 1. | 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. | 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. | 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. | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Palbociclib, PD-0332991, pharmacokinetics, breast cancer patients, Chinese