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

• ClinicalTrials.gov Identifier: NCT02499146
• Recruitment Status: Unknown
• First Posted: July 15, 2015
• Results First Posted: July 29, 2019
• Last Update Posted: July 29, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Advanced Breast Cancer	Drug: Palbociclib; Drug: Letrozole	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Masking: None (Open Label)
• Primary Purpose: Other
• 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
• Actual Study Start Date: September 11, 2015
• Actual Primary Completion Date: July 31, 2018
• Estimated Study Completion Date: January 26, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; Combination therapy of palbociclib and letrozole	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; Drug: Letrozole; 2.5 mg , orally once daily (continuously)

Outcome Measures

Primary Outcome Measures :

1. Single-dose Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) for Palbociclib [ Time Frame: 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.
2. Single-dose PK: Time to Reach Maximum Plasma Concentration (Tmax) for Palbociclib [ Time Frame: 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.
3. Single-dose PK: Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to the Time 10 Hours (AUC10) for Palbociclib [ Time Frame: 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.
4. Single-dose PK: AUC From Time 0 to the Time 24 Hours (AUC24) for Palbociclib [ Time Frame: 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.
5. Single-dose PK: AUC From Time 0 to the Time of Last Quantifiable Concentration (AUClast) for Palbociclib [ Time Frame: 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.
6. Single-dose PK: AUC From Time 0 Extrapolated to Infinite Time (AUCinf) for Palbociclib [ Time Frame: 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.
7. Single-dose PK: Rate Constant for Terminal Phase (Kel) for Palbociclib [ Time Frame: Lead-in phase: Day 1 pre-dose, 2, 4, 6, 8, 10, 24, 48, 72, 96 and 120 hours post dose ]
   Kel for palbociclibo in the single-dose part (lead-in phase) was obtained by linear regression of the log-linear concentration-time curve.
8. Single-dose PK: Mean Residence Time (MRT) for Palbociclib [ Time Frame: 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.
9. Single-dose PK: Terminal Half-Life (t1/2) for Palbociclib [ Time Frame: 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.
10. Single-dose PK: Apparent Oral Clearance (CL/F) for Palbociclib [ Time Frame: 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.
11. Single-dose PK: Apparent Volume of Distribution (Vz/F) for Palbociclib [ Time Frame: 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).
12. Multiple-dose PK: Maximum Plasma Concentration at Steady State (Css,Max) for Palbociclib [ 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 ]
    Css,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
13. Multiple-dose PK: Minimum Plasma Concentration at Steady State (Css,Min) for Palbociclib [ 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 ]
    Css,min of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
14. Multiple-dose PK: AUC Within a Dosing Interval of Tau (=24 Hours) at Steady State (AUCss,Tau) for Palbociclib [ 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 ]
    AUCss,tau of palbociclib in the multiple-dose part (Cycle 1) was determined by linear/log trapezoidal method.
15. Multiple-dose PK: Average Plasma Concentration at Steady State (Css,av) for Palbociclib [ 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 ]
    Css,av of palbociclib in the multiple-dose part (Cycle 1) was calculated as AUCss,tau/tau, where tau was 24 hours.
16. Multiple-dose PK: Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for Palbociclib [ 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 ]
    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.
17. Multiple-dose PK: Vz/F for Palbociclib [ 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 ]
    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.
18. Multiple-dose PK: t1/2 for Palbociclib [ 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 ]
    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.
19. Multiple-dose PK: CL/F for Palbociclib [ 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 ]
    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.
20. Multiple-dose PK: Peak to Trough Fluctuation at Steady State (PTF) for Palbociclib [ 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 ]
    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.
21. Observed Accumulation Ratio (Rac) for Palbociclib [ 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 ]
    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).
22. Steady State Accumulation Ratio (Rss) for Palbociclib [ 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 ]
    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).

Secondary Outcome Measures :

1. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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) ]
   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.
2. Number of Participants With Treatment-Emergent AEs by Maximum National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade [ Time Frame: up to 2.8 years by primary completion date of 31 July 2018 ]
   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.
3. Number of Participants With Laboratory Test Abnormalities [ Time Frame: up to 2.8 years by primary completion date of 31 July 2018 ]
   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.
4. Number of Participants Meeting the Categorical Summarization Criteria for QTcF and QTcB Parameters [ Time Frame: up to 2.8 years by primary completion date of 31 July 2018 ]
   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.
5. Progression-Free Survival (PFS) [ Time Frame: Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 ]
   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.
6. Percentage of Participants Achieving Objective Response (Objective Response Rate [ORR]) [ Time Frame: Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 ]
   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.
7. Percentage of Participants Achieving Disease Control (Disease Control Rate [DCR]) [ Time Frame: Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 ]
   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.
8. Duration of Response [ Time Frame: Every 12 weeks from Cycle 1 Day 1, up to 144 weeks by primary completion date of 31 July 2018 ]
   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.
9. 1-Year PFS Probability [ Time Frame: 1 year ]
   One-year PFS probability was defined as the probability (expressed as percentage) of PFS at 1 year after Cycle 1 Day 1.
10. Trough Plasma Concentration of Letrozole [ Time Frame: pre-dose of Cycle 1 Days 19, 20, 21 and Cycle 2 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.
11. Ratio Over Baseline for Skin Biomarker Phosphorylated Retinoblastoma Protein (pRb) Expression [ Time Frame: Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26 ]
    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.
12. Ratio Over Baseline for Skin Biomarker Ki67 Expression [ Time Frame: Baseline (Day -1), lead-in phase Days 1 and 2, Cycle 1 Days 21, 22, 23, 24, 25, 26 ]
    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.
13. Ratio Over Baseline for Thymidine Kinase (TK) Concentration [ 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 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Locations

China, Beijing

Beijing Cancer Hospital/Oncology department

Beijing, Beijing, China, 100142

China, Guangdong

Sun Yat-Sen University Cancer Center

Guangzhou, Guangdong, China, 510060

Guangdong General Hospital/Department of Breast Surgery

Guangzhou, Guangdong, China, 510080

China, Heilongjiang

Harbin Medical University Cancer Hospital

Harbin, Heilongjiang, China, 150081

China, Jilin

The first hospital of jilin university

Changchun, Jilin, China, 130021

China, Zhejiang

The First Affiliated Hospital of College of Medicine, Zhejiang University

Hangzhou, Zhejiang, China, 310003

China

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Beijing, China, 100021

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

  Study Documents (Full-Text)

Documents provided by Pfizer:

Study Protocol  [PDF] July 24, 2015

Statistical Analysis Plan  [PDF] May 16, 2016

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yu Y, Sun W, Liu Y, Wang D. Pharmacodynamic Modeling of CDK4/6 Inhibition-Related Biomarkers and the Characterization of the Relationship Between Biomarker Response and Progression-Free Survival in Patients With Advanced Breast Cancer. J Clin Pharmacol. 2022 Mar;62(3):376-384. doi: 10.1002/jcph.1971. Epub 2021 Nov 16.

Xu B, Li H, Zhang Q, Sun W, Yu Y, Li W, Wang S, Liao N, Shen P, Liu Y, Huang Y, Linn C, Zhao H, Jiang J, Wang D. Pharmacokinetics, safety, activity, and biomarker analysis of palbociclib plus letrozole as first-line treatment for ER+/HER2- advanced breast cancer in Chinese women. Cancer Chemother Pharmacol. 2021 Jul;88(1):131-141. doi: 10.1007/s00280-021-04263-9. Epub 2021 Apr 9.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02499146
• Other Study ID Numbers: A5481019
• First Posted: July 15, 2015
• Results First Posted: July 29, 2019
• Last Update Posted: July 29, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: 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.

Keywords provided by Pfizer:

Palbociclib; PD-0332991; pharmacokinetics; breast cancer patients; Chinese

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Letrozole; Palbociclib; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Protein Kinase Inhibitors