A Study Of Palbociclib (PD-0332991) + Letrozole VS. Placebo+ Letrozole For 1st Line Treatment Of Asian Postmenopausal Women With ER+/HER2- Advanced Breast Cancer [PALOMA-4]

Study Overview
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Brief Summary
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The study is designed to compare the clinical benefit following treatment with letrozole in combination with Palbociclib versus letrozole in combination with placebo in Asian postmenopausal women with ER(+)/HER2(-) advanced breast cancer who have not received prior systemic anti cancer therapies for their advanced/metastatic disease.

Official Title
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A MULTICENTER, RANDOMIZED, DOUBLE-BLIND PHASE 3 STUDY OF PALBOCICLIB (ORAL CDK 4/6 INHIBITOR) PLUS LETROZOLE VERSUS PLACEBO PLUS LETROZOLE FOR THE TREATMENT OF PREVIOUSLY UNTREATED ASIAN POSTMENOPAUSAL WOMEN WITH ER (+), HER2 (-) ADVANCED BREAST CANCER

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Letrozole
* Drug: Placebo
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult Asian women with locoregionally recurrent or metastatic disease not amenable to curative therapy Confirmed diagnosis of ER positive breast cancer No prior systemic anti-cancer therapy for advanced ER+ disease Postmenopausal women Measurable disease as per Response Evaluation Criterion in Solid Tumors [RECIST] or bone-only disease Eastern Cooperative Oncology Group [ECOG] 0-1 Adequate organ and marrow function Patient must agree to provide tumor tissue Exclusion Criteria: Confirmed diagnosis of HER2 positive disease Patients with advanced, symptomatic, visceral spread that are at risk of life threatening complication in the short term Known uncontrolled or symptomatic CNS metastases Prior neoadjuvant or adjuvant treatment with a non steroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment Prior treatment with any CDK 4/6 inhibitor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib + Letrozole<br>Palbociclib, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment in combination with Letrozole, 2.5mg, orally once daily (continuously) | Drug: Palbociclib<br>* Palbociclib, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>* Other names: PD-0332991;Drug: Letrozole<br>* Letrozole, 2.5mg, orally once daily (continuously)<br>|
| Active Comparator: Placebo + Letrozole<br>Placebo, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment in combination with Letrozole, 2.5mg, orally once daily (continuously). | Drug: Placebo<br>* Placebo, 125mg, orally once daily on Day 1 to Day 21 of every 28-day cycle followed by 7 days off treatment<br>Drug: Letrozole<br>* Letrozole, 2.5mg, orally once daily (continuously)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Based on Investigator's Assessment | PFS was based on Kaplan-Meier estimates. PFS was defined as the time from the date of randomization to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) as a 20% increase in the sum of of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. In this outcome measure, PFS was based on investigator's assessment. | Randomization up to 65 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Based on Blinded Independent Central Review (BICR) | PFS was based on Kaplan-Meier estimates. PFS was defined as time from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause in the absence of documented progressive disease, whichever occurs first. In this outcome measure, PFS was based on BICR. | Randomization up to 65 months | 
| Percentage of Participants Wiht Objective Response (OR) Based on Investigator Assessment | OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on investigator assessment. | Randomization up to 65 months | 
| Percentage of Participants With Objective Response (OR) Based on Investigator Assessment (Participants With Measureable Disease at Baseline) | OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on investigator assessment. | Randomization up to 65 months | 
| Percentage of Participants With Objective Response (OR) Based on Blinded Independent Central Review (BICR) | OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on BICR. | Randomization up to 65 months | 
| Percentage of Participants With Objective Response (OR) Based on Blinded Independent Central Review (BICR) (Participants With Measureable Disease at Baseline) | OR was defined as a complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 recorded from randomization until disease progression or death due to any cause. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, OR was based on BICR. | Randomization up to 65 months | 
| Duration of Response (DOR) Based on Investigator Assessment (Participants With Objective Disease Response) | DOR was defined as the time from the first documentation of objective tumor response (complete response [CR] or partial response [PR]) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. DOR data was censored on the date of the last tumor assessment on study for participants who did not have objective tumor progression and who did not die due to any cause while on study. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, DOR was based on investigator assessment. | Randomization up to 65 months | 
| Duration of Response (DOR) Based on Blinded Independent Central Review (BICR) (Participants With Objective Disease Response) | DOR was defined as the time from the first documentation of objective tumor response (complete response [CR] or partial response [PR]) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. DOR data was censored on the date of the last tumor assessment on study for participants who did not have objective tumor progression and who did not die due to any cause while on study. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. In this outcome measure, DOR was based on BICR. | Randomization up to 65 months | 
| Percentage of Participants With Disease Control/Clinical Benefit Response (DC/CBR) Based on Investigator Assessment | DC/CBR was defined as CR, PR, or stable disease (SD) >=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on investigator assessment. | Randomization up to 65 months | 
| Percentage of Participants With Disease Control/Clinical Benefit Response (DC/CBR) Based on Investigator Assessment (Participants With Measureable Disease at Baseline) | DC/CBR was defined as CR, PR, or stable disease (SD) >=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on investigator assessment. | Randomization up to 65 months | 
| Percentage of Participants With Disease Control/Clinical Benefit Response (DC/CBR) Based on Blinded Independent Central Review (BICR) | DC/CBR was defined as CR, PR, or stable disease (SD) >=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on BICR. | Randomization up to 65 months | 
| Percentage of Participants With Disease Control/Clinical Benefit Response (DC/CBR) Based on Blinded Independent Central Review (BICR) (Participants With Measureable Disease at Baseline) | DC/CBR was defined as CR, PR, or stable disease (SD) >=24 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) recorded in the time period between randomization and disease progression or death to any cause. CR was defined as complete disappearance of all target lesions except for nodal disease. All target nodes must decrease to normal size (short axis <10 mm). No new lesions. The PR was defined as greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No new lesions. SD was defined as not qualifying for CR, PR, PD. PD is defined using RECIST v1.1 as a 20% increase in the sum of of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. In this outcome measure, DC/CBR was based on BICR. | Randomization up to 65 months | 
| Overall Survival (OS) | OS was defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. OS was assessed using Kaplan-Meier methods. | Randomization up to 65 months | 
| 1-Year, 2-Year and 3-Year Survival Probability | OS was defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. The 1-year survival probability was estimated using the Kaplan-Meier method and a 2-sided 95% confidence interval (CI) for the log [-log(1 year survival probability)] was be calculated using a normal approximation, and then back transformed to give a CI for the 1-year survival probability itself. The 2-year, and 3-year survival probabilities were estimated similarly. | Randomization up to 65 months | 
| Number of Participants With Treatment-Emergent Adverse Events (All Causalities) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Participants were counted only once per treatment in each row. | Randomization up to 65 months | 
| Number of Participants With Treatment-Emergent Adverse Events (Treatment Related) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Relatedness to treatment was assessed by the investigator (Yes/No). Participants were counted only once per treatment in each row. | Randomization up to 65 months | 
| Number of Participants With Postbaseline Laboratory Abnormalities of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 (Participants With Baseline Laboratory Abnormalities of CTCAE Grade <=2) - Hematology | The laboratory results were graded according to the National Cancer Institute (NCI) CTCAE v4.0 severity grade. Shift tables were provided to examine the distribution of laboratory toxicities. The following hematology parameters had met the criteria of CTCAE grade shift change from Grade <=2 at baseline to Grade 3 or 4 post baseline: neutrophils (absolute), white blood cells, platelets, anemia and hemoglobin increased. | Randomization up to 65 months | 
| Number of Participants With Postbaseline Laboratory Abnormalities of Common Terminology Criteria for Adverse Events(CTCAE) Grade 3 or 4 (Participants With Baseline Laboratory Abnormalities of CTCAE Grade <=2) - Chemistry | The laboratory results were graded according to the National Cancer Institute (NCI) CTCAE v4.0 severity grade. Shift tables were provided to examine the distribution of laboratory toxicities. The following chemistry parameters had met the criteria of CTCAE grade shift change from Grade <=2 at baseline to Grade 3 or 4 post baseline: alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), bilirubin (total), creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, and hyponatremia. | Randomization up to 65 months | 
| Trough Plasma Concentration of Palbociclib | Summary of palbociclib trough concentrations | Pre-dose on Day 14 of Cycle 1 and Cycle 2 | 
| Model Estimated Mean Change From Baseline in Euro Quality of Life 5-Dimension Scale (EQ-5D) Index Scores | The EQ-5D is a 6-item instrument designed to assess health status in terms of a single index value or utility score. It consists of 5 descriptors of current health state (mobility, self care, usual activities, pain/discomfort, and anxiety/depression); a participant was asked to rate each state on a 3 level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher levels indicating greater severity/impairment. | Baseline up to Cycle 65 Day 1 | 
| Model Estimated Mean Change From Baseline in Euro Quality of Life (EQ) Visual Analog Scale (VAS) Scores | The EQ VAS recorded the participant's self rated questionnaire to assess generic health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). Published weights were available that allow for the creation of a single summary score. | Baseline up to Cycle 65 Day 1 | 
| Model Estimated Mean Changes From Baseline in Functional Assessment of Cancer Therapy - Breast (FACT-B) Total Score | The Functional Assessment of Cancer Therapy (FACT) is a modular approach to assess participant health related quality of life using a core set of questions (FACT-G) as well as a cancer site specific module. The FACT-G was a 27-item compilation of general questions divided into 4 domains: Physical Well Being, Social/Family Well Being, Emotional Well Being, and Functional Well Being. The FACT-B consists of the FACT-G (27 items) and a breast specific module: a 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to a 5-level scale ranging from 0=Not at all to 4=Very much. FACT-B total score = FACT-G + Breast Cancer Subscale. As each of the items ranges from 0-4, the range of possible scores is 0-148, with 0 being the worst possible score and 148 the best. A positive change of the total score indicated improvement from baseline and a negative change indicated deterioration. | Baseline up to Cycle 65 Day 1 | 
| Median Baseline Percent (%) Positive Cells for Ki67 | Archived formalin-fixed paraffin embedded (FFPE) specimen from the original diagnostic tumor tissue was collected and sent to the sponsor-designated central laboratories for assessment of Ki67 associated with sensitivity and/or resistance to Palbociclib. | Baseline | 
| Number of Participants With Detection in Estrogen Receptor (ER) | Archived formalin-fixed paraffin embedded (FFPE) specimen from the original diagnostic tumor tissue was collected and sent to the sponsor-designated central laboratories for assessment of ER associated with sensitivity and/or resistance to Palbociclib. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, postmenopausal women, estrogen-receptor positive, HER2 negative, locoregionally recurrent, metastatic