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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 26
- 试验地点
- 14
- 主要终点
- Single-dose PK: Terminal Half-Life (t1/2) for Palbociclib
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
Cohort 1
Combination therapy of palbociclib and letrozole
干预措施: Palbociclib (Drug)
Cohort 1
Combination therapy of palbociclib and letrozole
干预措施: Letrozole (Drug)
结局指标
主要结局
Single-dose PK: Terminal Half-Life (t1/2) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
t1/2 for palbociclib in the single-dose part (lead-in phase) was calculated as Loge(2)/kel.
Single-dose Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
Cmax of palbociclib in the single-dose part (lead-in phase) was observed directly from data.
Single-dose PK: Time to Reach Maximum Plasma Concentration (Tmax) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
Tmax for palbociclib in the single-dose part (lead-in phase) was observed directly from data as time of first occurrence.
Single-dose PK: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to the Time 10 Hours (AUC10) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, and 10 hours post dose
AUC10 for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
Single-dose PK: AUC From Time 0 to the Time 24 Hours (AUC24) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, and 24 hours post dose
AUC24 is AUCtau, where the dosing interval (tau) is 24 hours. AUC24 in the single-dose part (lead-in phase) for palbociclib was obtained by linear/log trapezoidal method.
Single-dose PK: AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
AUClast for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
Single-dose PK: AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
AUCinf for palbociclib in the single-dose part (lead-in phase) was calculated as AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel was the rate constant for terminal phase obtained by linear regression of the log-linear concentration-time curve.
Single-dose PK: Rate Constant for Terminal Phase (Kel) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
Kel for palbociclib in the single-dose part (lead-in phase) was obtained by linear regression of the log-linear concentration-time curve.
Single-dose PK: Mean Residence Time (MRT) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose
MRT for palbociclib in the single-dose part (lead-in phase) was calculated as AUMCinf/AUCinf, where AUMCinf was area under the first moment curve from time 0 to infinity.
Single-dose PK: Apparent Oral Clearance (CL/F) for Palbociclib
时间窗: 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.
Single-dose PK: Apparent Volume of Distribution (Vz/F) for Palbociclib
时间窗: 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).
Multiple-dose PK: Maximum Plasma Concentration at Steady State (Css,Max) for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21
Css,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
Multiple-dose PK: Minimum Plasma Concentration at Steady State (Css,Min) for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21
Css,min of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
Multiple-dose PK: AUC Within a Dosing Interval of Tau (=24 Hours) at Steady State (AUCss,Tau) for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21
AUCss,tau of palbociclib in the multiple-dose part (Cycle 1) was determined by linear/log trapezoidal method.
Multiple-dose PK: Average Plasma Concentration at Steady State (Css,av) for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21
Css,av of palbociclib in the multiple-dose part (Cycle 1) was calculated as AUCss,tau/tau, where tau was 24 hours.
Multiple-dose PK: Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21
Tss,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data as time of first occurrence within tau (=24 hours) at steady state.
Multiple-dose PK: Vz/F for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21
Vz/F of palbociclib in the multiple-dose part (Cycle 1) was calculated as Dose/(AUCss,tau \* kel), where AUCss,tau was the AUC within a dosing interval of tau (=24 hours) at steady state and kel was the terminal phase rate constant following multiple-dose calculated by a linear regression of the log-linear concentration-time curve.
Multiple-dose PK: t1/2 for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21
t1/2 of palbociclib in the multiple-dose part (Cycle 1) was calculated as ln (2)/kel, where kel was the terminal phase rate constant following multiple-dose calculated by a linear regression of the log-linear concentration-time curve.
Multiple-dose PK: CL/F for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21
CL/F of palbociclib in the multiple-dose part (Cycle 1) was calculated as Dose/AUCss,tau, where AUCss,tau was the AUC within a dosing interval of tau (=24 hours) at steady state.
Multiple-dose PK: Peak to Trough Fluctuation at Steady State (PTF) for Palbociclib
时间窗: Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24, 48, 72, 96, 120 hours post dose on Day 21
PTF of palbociclib in the multiple-dose part (Cycle 1) was determined as (Css,max - Css,min)/Css,av. Css,max and Css,min were observed directly from data while Css,av was calculated as AUCss,tau/tau, where tau was 24 hours.
Observed Accumulation Ratio (Rac) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, and 24 hours post dose; Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, and 24 hours post dose on Day 21
Rac of palbociclib was determined as AUCss,tau/AUCsd,tau, where AUCss,tau (tau=24 hours) was from multiple-dose part (Cycle 1) and AUCsd,tau was AUC24 from single-dose part (lead-in phase).
Steady State Accumulation Ratio (Rss) for Palbociclib
时间窗: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose; Cycle 1: pre-dose on Day 19, Day 20, Day 21, and 2, 4, 6, 8, 10, 24 hours post dose on Day 21
Rss of palbociclib was calculated as AUCss,tau/AUCinf, where AUCss,tau (tau=24 hours) was from multiple-dose part (Cycle 1) and AUCinf was from single-dose part (lead-in phase).
次要结局
- Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)(From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks))
- Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade(From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks))
- Number of Participants With Laboratory Test Abnormalities(From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks))
- Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters(From first dose of study medication up to 28 days after last dose of study medication (up to maximum of 475 weeks, maximum treatment exposure = 471 weeks))
- Progression-Free Survival (PFS)(From C1D1 to date of first documentation of PD or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure))
- Percentage of Participants Achieving Objective Response (Objective Response Rate [ORR])(From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure))
- Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR])(From C1D1 until disease progression or death due to any cause, whichever occurred first (up to maximum of 471 weeks of treatment exposure))
- Duration of Response(From first documentation of CR or PR to date of first documentation of objective progression or death, whichever occurred first (up to maximum of 471 weeks of treatment exposure))
- 1-Year PFS Probability(1 year)
- Trough Plasma Concentration of Letrozole(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(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(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(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)