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

Advanced Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02499146
• Other study ID #: A5481019
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: September 11, 2015
• Est. completion date: January 30, 2023

Study information

• Verified date: June 2022
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 26
• Est. completion date: January 30, 2023
• Est. primary completion date: July 31, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 65 Years

Eligibility

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).

Related Conditions & MeSH terms

• Advanced Breast Cancer
• Breast Neoplasms

Intervention

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
• Letrozole
2.5 mg , orally once daily (continuously)

Locations

Country	Name	City	State
China	Beijing Cancer Hospital/Oncology department	Beijing	Beijing
China	Cancer Institute and Hospital, Chinese Academy of Medical Sciences	Beijing
China	The first hospital of jilin university	Changchun	Jilin
China	Guangdong General Hospital/Department of Breast Surgery	Guangzhou	Guangdong
China	Sun Yat-Sen University Cancer Center	Guangzhou	Guangdong
China	The First Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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