Metastatic Breast Cancer
Conditions
Keywords
Palbociclib, Capecitabine, Hormonal Receptor positive, HER2 negative, Metastatic Breast Cancer, Resistance to non-steroidal Aromatase inhibitors, Fulvestrant, Exemestane, Aromatase inhibitor
Brief summary
This is an international (4 countries) randomized phase III study with 2 cohorts, patients will be randomized 1:1 to endocrine therapy (cohort 1: exemestane 25 mg daily, cohort 2: fulvestrant 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2 MBC are eligible if resistant to previous nonsteroidal aromatase inhibitors (NSAI) (letrozole or anastrozole) in cohort 1 or previous aromatase inhibitors (AI) (letrozole, anastrozole or exemestane) in cohort 2 defined as: recurrence while on or within 12 months after the end of adjuvant treatment with NSAI/AI or progression while on or within 1 month after the end of treatment with NSAI/AI for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic or mixed, in the absence of measurable disease.
Detailed description
296 patients have been randomized 1:1 between the experimental arm (Arm A: approximately 125 patients treated with palbociclib plus exemestane) and the control arm (Arm B: approximately 125 patients treated with capecitabine) before the approval of this protocol version (Cohort 1). Approximately 300 patients will be randomized 1:1 between the experimental arm (Arm A: approximately 150 patients treated with palbociclib plus fulvestrant) and the control arm (Arm B: approximately 150 patients treated with capecitabine) from the approval of this protocol version (Cohort 2).
Interventions
DRUGPalbociclib
DRUGCapecitabine
DRUGExemestane
DRUGFulvestrant
Sponsors
Pfizer
AstraZeneca
Spanish Breast Cancer Research Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The patient has signed the informed consent document. 2. a) Patients in cohort 1: Females with histologically confirmed MBC whose disease is resistant to previous non-steroidal aromatase inhibitors (letrozole or anastrozole) b) Patients in cohort 2: Females with histologically confirmed MBC whose disease was resistant to previous aromatase inhibitors (exemestane, letrozole or anastrozole). Resistance is defined as: Recurrence while on or within 12 months after the end of adjuvant treatment with NSAI/AI or Progression while on or within 1 month after the end of treatment with NSAI/AI for advanced disease. 3. Previous chemotherapy is permitted either in the (neo) adjuvant setting and/or first line therapy for MBC (chemotherapy administered as second adjuvant therapy for locoregional recurrence should be considered as first line chemotherapy for MBC). 4. It is not mandatory to have exemestane, letrozole or anastrozole as the most recent treatment before randomization but recurrence or progression of breast cancer while receiving (or immediately after the enf of) the most recent systemic therapy has to be documented before randomization. 5. Hormonal receptor positive (HR+) breast cancer based on local laboratory determination. HR+ defined as major or equal to 1 percent positive cells by Immunohistochemistry (IHC) for ER and/or Progesterone Receptor (PgR). 6. Documented HER2 negative breast cancer based on local laboratory determination on most recent tumor biopsy. HER2 negative tumor is determined as IHC score 0 or 1+ or negative by ISH (FISH/Chromogenic In Situ Hybridization (CISH)/SISH) defined as a HER2/CEP17 ratio minor to 2 or for single probe assessment a HER2 copy number minor to 4. 7. Measurable disease or at least one bone lesion, lytic or mixed (lytic+blastic), which has not been previously irradiated and is assessable by CT/MRI in the absence of measurable disease according to RECIST 1.1 criteria. 8. Patient is at least 18 years of age. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status minor or equal to 1. 10. Life expectancy major or equal to 12 weeks. 11. Adequate organ and bone marrow function. 12. Postmenopausal women defined as women with: Prior bilateral surgical oophorectomy, or Age \> 60 years, or Age \< 60 years and 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 or follicle-stimulating hormone (FSH) and estradiol blood levels in their respective postmenopausal ranges 13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade minor or equal to 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion). 14. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion criteria
1. Have received more than 1 prior chemotherapy regimen for MBC. (NOTE: Chemotherapy administered as second adjuvant therapy for locoregional recurrence should be considered one prior chemotherapy for MBC).Other previous anticancer endocrine treatments for advanced disease are allowed. 2. 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). 3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (eg, radiotherapy,) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before randomization. 4. Prior treatment with any CDK4/6, mTOR or PI3K inhibitor (any agent whose mechanism of action is to inhibit the PI3 kinase-mTOR pathway) or capecitabine. 5. a) Patients included in cohort 1: Prior treatment with exemestane in the metastatic setting. If the patient has received exemestane in the adjuvant setting and developed MBC, she will be eligible for the study provided: * She has received letrozole/anastrozole as first-line MBC and progressed. * At least 1 year has elapsed since the end of adjuvant exemestane treatment. b) Patients included in Cohort 2: Prior treatment with fulvestrant in the metastatic setting. If the patient has received fulvestrant in the adjuvant setting and developed MBC, she will be eligible for the study provided: * She has received letrozole/anastrozole as first-line MBC and progressed. * At least 1 year has elapsed since the end of adjuvant fulvestrant treatment. 6. Patients treated within the last 7 days prior to randomization with: * Food or drugs that are known to be CYP3A4 inhibitors * Drugs that are known to be CYP3A4 inducers * Drugs that are known to prolong the QT interval 7. Patients who received before randomization: * Any investigational agent within 4 weeks * Chemotherapy within a period of time that is minor than the cycle length used for that treatment (e.g. less 3 weeks for fluorouracil, doxorubicine, epirubicin or less than 1 week for weekly chemotherapy) * Previous endocrine therapy is permitted without any window * Radiotherapy within 2 weeks (all acute toxic effects must be resolved to NCI CTCAE version 4.0 grade minor 1, except toxicities not considered a safety risk for the patient at investigator´s discretion) but patients who received prior radiotherapy to less than 25 per cent of bone marrow are not eligible independent of when it was received * Major surgery or other anti-cancer therapy not previously specified within 4 weeks, (all acute toxic effects must be resolved to NCI CTCAE version 4.0 grade minor 1, except toxicities not considered a safety risk for the patient at investigator´s discretion) 8. Diagnosis of any other malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. 9. QTc major 480msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP). 10. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (eg, hypocalcemia, hypokalemia, hypomagnesemia). 11. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade major or equal to 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism. 12. Difficulties to swallow tablets, malabsorption syndrome disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or active inflammatory bowel disease or chronic diarrhea. 13. Known hypersensitivity to exemestane, palbociclib, capecitabine, fulvestrant or any of their excipients. 14. Any of the following contraindications for chemotherapy with capecitabine: * Known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase. * Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically related analogues, such as brivudine. 15. Only for patients in Cohort 2 any of the following contraindications for treatment with fulvestrant: \- Bleeding diathesis (i.e., disseminated intravascular coagulation, clotting factor deficiency) or long-term anticoagulant therapy (other than antiplatelet therapy and low dose warfarin) provided that the International Normalised Ratio (INR) is less than 1.6. 16. Known human immunodeficiency virus infection. 17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. 18. Recent or active suicidal ideation or behavior
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Through study treatment, and average of 8 months | The primary efficacy variable is PFS based on the investigator's assessment. PFS is defined as the time from randomization to the first documented progressive disease based on the investigator's assessment, using RECIST version 1.1, or death from any cause, whichever occurs first. Estrogen Receptor 1 (ESR1) mutational status will be determined in circulating free DNA (cDNA) obtained from. Disease assessments will be performed at baseline and every 8 weeks (± 7 days) from the start of treatment and every 12 weeks (±7 days) after 120 weeks of treatment baseline plasma samples and will be prospectively determined before the interims or final analyses. ESR1 mutational status will be blinded to the patients, investigators and study team. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS Estrogen Receptor 1 (ESR1) Wild Type | From randomization date to date of first documentation of progression or death (an average of 8 months) | PFS is defined as the time from randomization to the first documented progressive disease based on the investigator's assessment, using RECIST version 1.1, or death from any cause, whichever occurs first. PFS data will be censored on the date of the last tumor assessment on study for patients who do not have objective tumor progression and who do not die while on study. Patients lacking an evaluation of tumor response after randomization will have their PFS time censored on the date of randomization with 1 day duration. Additionally, patients who start a new anti-cancer therapy prior to documented PD will be censored at the date of the last tumor assessment prior to the start of the new therapy. |
| Overall Survival (OS) ESR1 Wild Type | From randomization until death (up to approximately 34 months) | OS is defined as the time from the date of randomization to the date of death from any cause. |
| Objective Response Rate (ORR) ESR1 Wild Type | Through study treatment, and average of 8 months | Complete Response (CR) plus Partial Response (PR) based on the investigator's assessment according to the RECIST version 1.1 in patients randomized with measurable disease. Tumor assessment will be performed at baseline, the same method of measurement used at baseline will be used for further evaluations, that will be conducted every 8 weeks (±7days). The best response across treatment will be recorded. OR is defined as the complete plus partial responses out of the patients who had measurable disease at baseline. |
| Clinical Benefit Rate (CBR) ESR1 Wild Type | Through study treatment, and average of 8 months | CB is defined as complete response (CR), partial response (PR), or stable disease (SD) based on the investigator´s assessment lasting more than 24 weeks according to the RECIST version 1.1 in all randomized patients (ITT population). Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR. |
| Response Duration (RD) ESR1 Wild Type | Through study treatment, and average of 8 months | Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| The Number of Participants Who Experienced Adverse Events (AE) | Through study treatment, and average of 8 months | Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0. Safety assessments were performed at baseline and during the study: Vital signs (blood pressure, pulse, temperature), Laboratory (hemoglobin, White Blood Cell, Absolute Neutrophils, platelet count, fasting glucose, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, sodium, potassium, magnesium, total calcium. AEs were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03. |
| Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | The EORTC QLQ C30 is a 30 item questionnaire composed of functional scales, a global health/quality of life and cancer related symptoms. All of the scales and single-item measures range are scored from 0 to 100. A high scale score represents a high / healthy level of functioning. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-C30 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis. |
| Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | The EORTC QLQ C30 is a 30 item questionnaire composed of functional scales, a global health/quality of life and cancer related symptoms. All of the scales and single-item measures range are scored from 0 to 100. A high scale score represents a high level of symptomatology / problems. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-C30 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis. |
| Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | The EORTC QLQ BR23 is a 23 item breast cancer specific companion module to the EORTC QLQ C30 and consists of functional scales and symptom subscales. All of the scales and single-item measures range are scored from 0 to 100. A high score for the functional scales represents a high/healthy level of functioning. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-BR23 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis. |
| Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | The EORTC QLQ BR23 is a 23 item breast cancer specific companion module to the EORTC QLQ C30 and consists of functional scales and symptom subscales. All of the scales and single-item measures range are scored from 0 to 100. A high score for the functional scales represents a high level of symptomatology / problems. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-BR23 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis. |
| Overall Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment. An average of 8 months, an average of 1 year, and an average of 2 years. | EQ 5D is a 6 item instrument which assess health status in terms of a single index value. Consists of 5 descriptors of current health state (mobility, self-care, usual activities, pain/discomfort, anxiety/depression); patient is asked to rate each state on 3 level scale (1=no problem, 2=some problem, 3=extreme problem). Higher levels indicating greater severity/impairment. It includes a visual analogue scale (EQ VAS) which records patient's self-rated health on a scale from 0 (worst imaginable) to 100 (best imaginable). Published weights allows for the creation of a single summary score. Overall scores range from 0 to 1 (low score=higher level of dysfunction, 1=perfect health). The change from baseline of EQ-5D subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis. |
| Overall Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment. An average of 8 months, an average of 1 year, and an average of 2 years. | The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). The change from baseline of EQ-5D subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis. |
| Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration. Deterioration is defined as a change from baseline ≥ minimally important difference (MID) as a change from baseline ≤ -MID for EORTC QLQ-C30 functional scales, global health status/QOL score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1. |
| Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration. Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for EORTC QLQ-C30 symptom scores. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1. 999 means value not estimated. |
| Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for QLQ-BR23 score \[(date of first detection of deterioration - date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for QLQ-BR23 score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1. Sexual functioning and Sexual enjoyment could not be estimated due to lack of response. 999 means value not estimated. |
| Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale | Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months. | Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for QLQ-BR23 score \[(date of first detection of deterioration - date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for QLQ-BR23 score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1. Upset by hair loss could not be estimated due to lack of response. |
Countries
Austria, Hungary, Israel, Spain
Participant flow
Recruitment details
92 patients were screening failure. A total of 601 patients were included in this study from March 2014 to July 2018. Cohort 1 included 296 patients (153 on palbociclib plus exemestane and 143 on capecitabine) and cohort 2 included 305 patients (149 on palbociclib plus fulvestrant and 156 on capecitabine).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Palbociclib Plus Exemestane \- Cohort 1:Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Exemestane 25 mg orally once daily.
Palbociclib
Exemestane | 153 |
| Cohort 1:Capecitabine Cohort 1: Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.
Capecitabine | 143 |
| Cohort 2: Palbociclib Plus Fulvestrant \- Cohort 2: Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.
Palbociclib
Fulvestrant | 149 |
| Cohort 2:Capecitabine Cohort 2:Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.
Capecitabine | 156 |
| Total | 601 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 25 | 3 | 16 |
| Overall Study | Death | 1 | 0 | 1 | 3 |
| Overall Study | Enzyme defect | 0 | 0 | 0 | 1 |
| Overall Study | Ongoing at date of cut-off 30-May-2019 | 10 | 5 | 37 | 28 |
| Overall Study | Patient Required Therapy/Procedure Not Permitted | 0 | 1 | 0 | 1 |
| Overall Study | Patient was not able to take whole dose of capecitabine | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 4 | 0 | 0 |
| Overall Study | Progressive Disease | 122 | 90 | 102 | 89 |
| Overall Study | Protocol Violation | 2 | 4 | 1 | 3 |
| Overall Study | Randomized But Not Treated | 3 | 6 | 0 | 4 |
| Overall Study | Second Invasive Primary Malignancy | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 8 | 5 | 9 |
Baseline characteristics
| Characteristic | Total | Cohort 2:Capecitabine | Cohort 1: Palbociclib Plus Exemestane | Cohort 2: Palbociclib Plus Fulvestrant | Cohort 1:Capecitabine |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 210 Participants | 53 Participants | 56 Participants | 56 Participants | 45 Participants |
| Age, Categorical Between 18 and 65 years | 391 Participants | 103 Participants | 97 Participants | 93 Participants | 98 Participants |
| Age, Continuous | 60 years | 60 years | 60 years | 62 years | 60 years |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 0 | 352 Participants | 93 Participants | 85 Participants | 90 Participants | 84 Participants |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 1 | 249 Participants | 63 Participants | 68 Participants | 59 Participants | 59 Participants |
| ESR1 mutational status Mutant | 164 Participants | 48 Participants | 41 Participants | 38 Participants | 37 Participants |
| ESR1 mutational status Not available | 44 Participants | 10 Participants | 8 Participants | 9 Participants | 17 Participants |
| ESR1 mutational status Wild-type | 393 Participants | 98 Participants | 104 Participants | 102 Participants | 89 Participants |
| Histologic grade G1, Well Differentiated | 59 Participants | 14 Participants | 17 Participants | 13 Participants | 15 Participants |
| Histologic grade G2, Moderately Differentiated | 267 Participants | 72 Participants | 68 Participants | 70 Participants | 57 Participants |
| Histologic grade G3, Poorly Differentiated | 151 Participants | 40 Participants | 36 Participants | 38 Participants | 37 Participants |
| Histologic grade GX, Unknown | 84 Participants | 19 Participants | 23 Participants | 19 Participants | 23 Participants |
| Histologic grade Not Available/Not Done | 40 Participants | 11 Participants | 9 Participants | 9 Participants | 11 Participants |
| Histopathology type Breast Invasive Ductal Carcinoma | 481 Participants | 125 Participants | 122 Participants | 117 Participants | 117 Participants |
| Histopathology type Breast Invasive Lobular Carcinoma | 91 Participants | 20 Participants | 23 Participants | 24 Participants | 24 Participants |
| Histopathology type Not Available/Not Done | 13 Participants | 3 Participants | 5 Participants | 4 Participants | 1 Participants |
| Histopathology type Other | 16 Participants | 8 Participants | 3 Participants | 4 Participants | 1 Participants |
| Hormone receptor status ER negative and PR positive or ER positive and PR not available | 11 Participants | 5 Participants | 2 Participants | 2 Participants | 2 Participants |
| Hormone receptor status ER positive and PR negative | 140 Participants | 33 Participants | 36 Participants | 33 Participants | 38 Participants |
| Hormone receptor status Estrogen-receptor (ER) positive and progesterone-receptor (PR) positive | 449 Participants | 118 Participants | 114 Participants | 114 Participants | 103 Participants |
| Hormone receptor status Triple negative | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Line at study entry 1st line | 139 Participants | 43 Participants | 27 Participants | 38 Participants | 31 Participants |
| Line at study entry 2nd line | 268 Participants | 79 Participants | 63 Participants | 76 Participants | 50 Participants |
| Line at study entry ≥3rd line | 194 Participants | 34 Participants | 63 Participants | 35 Participants | 62 Participants |
| Number of prior lines of endocrine therapy for metastatic breast cancer (MBC) 1 | 327 Participants | 90 Participants | 82 Participants | 85 Participants | 70 Participants |
| Number of prior lines of endocrine therapy for metastatic breast cancer (MBC) 2 | 90 Participants | 9 Participants | 35 Participants | 12 Participants | 34 Participants |
| Number of prior lines of endocrine therapy for metastatic breast cancer (MBC) 3 | 9 Participants | 1 Participants | 3 Participants | 1 Participants | 4 Participants |
| Number of prior lines of endocrine therapy for metastatic breast cancer (MBC) Combination | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Number of prior lines of endocrine therapy for metastatic breast cancer (MBC) Maintenance after chemotherapy | 31 Participants | 12 Participants | 3 Participants | 12 Participants | 4 Participants |
| Number of prior lines of endocrine therapy for metastatic breast cancer (MBC) No prior endocrine therapy for MBC | 143 Participants | 44 Participants | 30 Participants | 38 Participants | 31 Participants |
| Prior chemotherapy for MBC No | 430 Participants | 115 Participants | 105 Participants | 108 Participants | 102 Participants |
| Prior chemotherapy for MBC Yes | 171 Participants | 41 Participants | 48 Participants | 41 Participants | 41 Participants |
| Race/Ethnicity, Customized Hispanic Or Latino | 75 Participants | 18 Participants | 20 Participants | 16 Participants | 21 Participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino | 511 Participants | 136 Participants | 128 Participants | 129 Participants | 118 Participants |
| Race/Ethnicity, Customized Unknown | 15 Participants | 2 Participants | 5 Participants | 4 Participants | 4 Participants |
| Region of Enrollment Austria | 15 participants | 5 participants | 5 participants | 4 participants | 1 participants |
| Region of Enrollment Hungary | 59 participants | 19 participants | 10 participants | 22 participants | 8 participants |
| Region of Enrollment Israel | 39 participants | 14 participants | 7 participants | 12 participants | 6 participants |
| Region of Enrollment Spain | 488 participants | 118 participants | 131 participants | 111 participants | 128 participants |
| Sensitivity to prior endocrine therapy No | 149 Participants | 34 Participants | 46 Participants | 30 Participants | 39 Participants |
| Sensitivity to prior endocrine therapy Yes | 452 Participants | 122 Participants | 107 Participants | 119 Participants | 104 Participants |
| Sex: Female, Male Female | 601 Participants | 156 Participants | 153 Participants | 149 Participants | 143 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Status at initial diagnosis M0: Cancer has not spread to other parts of the body | 471 Participants | 120 Participants | 127 Participants | 115 Participants | 109 Participants |
| Status at initial diagnosis M1: Cancer has spread to other parts of the body | 130 Participants | 36 Participants | 26 Participants | 34 Participants | 34 Participants |
| Visceral disease No | 204 Participants | 54 Participants | 50 Participants | 52 Participants | 48 Participants |
| Visceral disease Not available | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Visceral disease Yes | 396 Participants | 102 Participants | 103 Participants | 97 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 85 / 150 | 43 / 149 | 116 / 289 |
| other Total, other adverse events | 147 / 150 | 148 / 149 | 286 / 289 |
| serious Total, serious adverse events | 34 / 150 | 21 / 149 | 72 / 289 |
Outcome results
Primary
Progression-Free Survival (PFS)
The primary efficacy variable is PFS based on the investigator's assessment. PFS is defined as the time from randomization to the first documented progressive disease based on the investigator's assessment, using RECIST version 1.1, or death from any cause, whichever occurs first. Estrogen Receptor 1 (ESR1) mutational status will be determined in circulating free DNA (cDNA) obtained from. Disease assessments will be performed at baseline and every 8 weeks (± 7 days) from the start of treatment and every 12 weeks (±7 days) after 120 weeks of treatment baseline plasma samples and will be prospectively determined before the interims or final analyses. ESR1 mutational status will be blinded to the patients, investigators and study team.
Time frame: Through study treatment, and average of 8 months
Population: The Intent to treat population (ITT) include all patients who were randomized, with study drug/medication assignment designated according to initial randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Progression-Free Survival (PFS) | 7.3 month |
| Cohort 1: Capecitabine | Progression-Free Survival (PFS) | 9.4 month |
| Cohort 2: Palbociclib Plus Fulvestrant | Progression-Free Survival (PFS) | 7.5 month |
| Cohort 2: Capecitabine | Progression-Free Survival (PFS) | 10 month |
Secondary
Clinical Benefit Rate (CBR) ESR1 Wild Type
CB is defined as complete response (CR), partial response (PR), or stable disease (SD) based on the investigator´s assessment lasting more than 24 weeks according to the RECIST version 1.1 in all randomized patients (ITT population). Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.
Time frame: Through study treatment, and average of 8 months
Population: ESR1 wild type population include patients with ESR1 mutational status as wild type at study entry.~* Exemestane or Fulvestrant plus Palbociclib ESR1 wild type population: Cohort 1 (n=153) of which ESR1 wild type (n=104) and cohort 2 (n=149) of which ESR1 wild type (n=102). Total ESR1 wild type 206~* Capecitabine ESR1 wild type population: Cohort 1 (n=143) of which ESR1 wild type (n=89) and cohort 2 (n=156) of which ESR1 wild type (n=98). Total ESR1 wild type 187
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Clinical Benefit Rate (CBR) ESR1 Wild Type | 157 Participants |
| Cohort 1: Capecitabine | Clinical Benefit Rate (CBR) ESR1 Wild Type | 154 Participants |
Secondary
Objective Response Rate (ORR) ESR1 Wild Type
Complete Response (CR) plus Partial Response (PR) based on the investigator's assessment according to the RECIST version 1.1 in patients randomized with measurable disease. Tumor assessment will be performed at baseline, the same method of measurement used at baseline will be used for further evaluations, that will be conducted every 8 weeks (±7days). The best response across treatment will be recorded. OR is defined as the complete plus partial responses out of the patients who had measurable disease at baseline.
Time frame: Through study treatment, and average of 8 months
Population: ESR1 wild type population include patients with ESR1 mutational status as wild type at study entry.~* Exemestane or Fulvestrant plus Palbociclib ESR1 wild type population: Cohort 1 (n=153) of which ESR1 wild type (n=104) and cohort 2 (n=149) of which ESR1 wild type (n=102). Total ESR1 wild type 206~* Capecitabine ESR1 wild type population: Cohort 1 (n=143) of which ESR1 wild type (n=89) and cohort 2 (n=156) of which ESR1 wild type (n=98). Total ESR1 wild type 187
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Objective Response Rate (ORR) ESR1 Wild Type | 47 Participants |
| Cohort 1: Capecitabine | Objective Response Rate (ORR) ESR1 Wild Type | 55 Participants |
Secondary
Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores
The EORTC QLQ BR23 is a 23 item breast cancer specific companion module to the EORTC QLQ C30 and consists of functional scales and symptom subscales. All of the scales and single-item measures range are scored from 0 to 100. A high score for the functional scales represents a high level of symptomatology / problems. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-BR23 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Systemic therapy side effects | 5.61 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Breast symptoms | -0.42 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Arm symptoms | -2.26 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Upset by hair loss | 8.35 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Upset by hair loss | -1.96 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Systemic therapy side effects | 4.49 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Arm symptoms | -2.09 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores | Breast symptoms | -2.00 units on a scale |
Secondary
Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores
The EORTC QLQ C30 is a 30 item questionnaire composed of functional scales, a global health/quality of life and cancer related symptoms. All of the scales and single-item measures range are scored from 0 to 100. A high scale score represents a high level of symptomatology / problems. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-C30 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Nausea and vomiting | 1.65 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Appetite loss | 2.99 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Dyspnoea | 2.73 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Constipation | 3.91 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Pain | -1.79 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Diarrhoea | 3.67 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Insomnia | -3.04 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Financial difficulties | -1.31 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Fatigue | 3.85 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Financial difficulties | 1.73 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Fatigue | 5.79 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Nausea and vomiting | 1.45 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Pain | -1.90 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Dyspnoea | -0.05 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Insomnia | -5.94 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Appetite loss | 1.04 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Constipation | -1.45 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores | Diarrhoea | 6.73 units on a scale |
Secondary
Overall Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale
The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). The change from baseline of EQ-5D subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment. An average of 8 months, an average of 1 year, and an average of 2 years.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale | 67.1 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale | 66.6 units on a scale |
Secondary
Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores
The EORTC QLQ BR23 is a 23 item breast cancer specific companion module to the EORTC QLQ C30 and consists of functional scales and symptom subscales. All of the scales and single-item measures range are scored from 0 to 100. A high score for the functional scales represents a high/healthy level of functioning. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-BR23 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Body image | -1.83 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Sexual functioning | 2.94 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Sexual enjoyment | -6.32 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Future perspective | 13.80 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Future perspective | 15.22 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Body image | 0.14 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Sexual enjoyment | -4.32 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | Sexual functioning | 1.72 units on a scale |
Secondary
Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores
The EORTC QLQ C30 is a 30 item questionnaire composed of functional scales, a global health/quality of life and cancer related symptoms. All of the scales and single-item measures range are scored from 0 to 100. A high scale score represents a high / healthy level of functioning. Change from baseline has been calculated as each visit score minus baseline score. The change from baseline of EORTC QLQ-C30 subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Global health status / QoL | 3.28 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Physical functioning | -1.73 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Role functioning | -1.09 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Emotional functioning | 6.78 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Cognitive functioning | -2.18 units on a scale |
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Social functioning | -0.67 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Cognitive functioning | -2.42 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Global health status / QoL | 1.97 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Emotional functioning | 8.67 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Physical functioning | -2.94 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Social functioning | -3.01 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | Role functioning | -4.97 units on a scale |
Secondary
Overall Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores
EQ 5D is a 6 item instrument which assess health status in terms of a single index value. Consists of 5 descriptors of current health state (mobility, self-care, usual activities, pain/discomfort, anxiety/depression); patient is asked to rate each state on 3 level scale (1=no problem, 2=some problem, 3=extreme problem). Higher levels indicating greater severity/impairment. It includes a visual analogue scale (EQ VAS) which records patient's self-rated health on a scale from 0 (worst imaginable) to 100 (best imaginable). Published weights allows for the creation of a single summary score. Overall scores range from 0 to 1 (low score=higher level of dysfunction, 1=perfect health). The change from baseline of EQ-5D subscales have been analyzed using linear mixed models, including treatment group, visit, the interaction between treatment group and visit, baseline score and stratification factors as covariates. Overall mean of change and CI 95% has been retrieved from this analysis.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment. An average of 8 months, an average of 1 year, and an average of 2 years.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Overall Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores | 0.72 units on a scale |
| Cohort 1: Capecitabine | Overall Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores | 0.71 units on a scale |
Secondary
Overall Survival (OS) ESR1 Wild Type
OS is defined as the time from the date of randomization to the date of death from any cause.
Time frame: From randomization until death (up to approximately 34 months)
Population: ESR1 wild type population include patients with ESR1 mutational status as wild type at study entry.~* Exemestane or Fulvestrant plus Palbociclib ESR1 wild type population: Cohort 1 (n=153) of which ESR1 wild type (n=104) and cohort 2 (n=149) of which ESR1 wild type (n=102). Total ESR1 wild type 206~* Capecitabine ESR1 wild type population: Cohort 1 (n=143) of which ESR1 wild type (n=89) and cohort 2 (n=156) of which ESR1 wild type (n=98). Total ESR1 wild type 187
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Overall Survival (OS) ESR1 Wild Type | 33.7 months |
| Cohort 1: Capecitabine | Overall Survival (OS) ESR1 Wild Type | 32 months |
Secondary
PFS Estrogen Receptor 1 (ESR1) Wild Type
PFS is defined as the time from randomization to the first documented progressive disease based on the investigator's assessment, using RECIST version 1.1, or death from any cause, whichever occurs first. PFS data will be censored on the date of the last tumor assessment on study for patients who do not have objective tumor progression and who do not die while on study. Patients lacking an evaluation of tumor response after randomization will have their PFS time censored on the date of randomization with 1 day duration. Additionally, patients who start a new anti-cancer therapy prior to documented PD will be censored at the date of the last tumor assessment prior to the start of the new therapy.
Time frame: From randomization date to date of first documentation of progression or death (an average of 8 months)
Population: ESR1 wild type population include patients with ESR1 mutational status as wild type at study entry.~* Exemestane or Fulvestrant plus Palbociclib ESR1 wild type population: Cohort 1 (n=153) of which ESR1 wild type (n=104) and cohort 2 (n=149) of which ESR1 wild type (n=102). Total ESR1 wild type 206~* Capecitabine ESR1 wild type population: Cohort 1 (n=143) of which ESR1 wild type (n=89) and cohort 2 (n=156) of which ESR1 wild type (n=98). Total ESR1 wild type 187
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | PFS Estrogen Receptor 1 (ESR1) Wild Type | 8.0 months |
| Cohort 1: Capecitabine | PFS Estrogen Receptor 1 (ESR1) Wild Type | 10.6 months |
Secondary
Response Duration (RD) ESR1 Wild Type
Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Through study treatment, and average of 8 months
Population: Safety population includes all patients randomized in the study who received at least one dose of treatment, according to the actual treatment received.~Patients from Safety Population with Measurable Disease and Best Response Complete or Partial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Response Duration (RD) ESR1 Wild Type | 9.7 months |
| Cohort 1: Capecitabine | Response Duration (RD) ESR1 Wild Type | 11.2 months |
Secondary
The Number of Participants Who Experienced Adverse Events (AE)
Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). Adverse events grade will be defined by the NCI CTCAE v4.0. Safety assessments were performed at baseline and during the study: Vital signs (blood pressure, pulse, temperature), Laboratory (hemoglobin, White Blood Cell, Absolute Neutrophils, platelet count, fasting glucose, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, sodium, potassium, magnesium, total calcium. AEs were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03.
Time frame: Through study treatment, and average of 8 months
Population: Safety population include patients randomized in the study who received at least one dose of treatment, according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | The Number of Participants Who Experienced Adverse Events (AE) | 147 Participants |
| Cohort 1: Capecitabine | The Number of Participants Who Experienced Adverse Events (AE) | 148 Participants |
| Cohort 2: Palbociclib Plus Fulvestrant | The Number of Participants Who Experienced Adverse Events (AE) | 286 Participants |
Secondary
Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale
Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for QLQ-BR23 score \[(date of first detection of deterioration - date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for QLQ-BR23 score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1. Sexual functioning and Sexual enjoyment could not be estimated due to lack of response. 999 means value not estimated.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale | Body image | 8.1 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale | Future perspective | 28.1 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale | Body image | 7 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale | Future perspective | 47.8 months |
Comparison: This Statistical Analysis corresponds to Body image scalep-value: 0.65995% CI: [0.74, 1.21]Regression, Cox
Comparison: This Statistical Analysis corresponds to Future perspective scalep-value: 0.92895% CI: [0.74, 1.39]Regression, Cox
Secondary
Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale
Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for QLQ-BR23 score \[(date of first detection of deterioration - date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for QLQ-BR23 score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1. Upset by hair loss could not be estimated due to lack of response.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale | Systemic side-effects | 4 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale | Breast symptoms | 11.1 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale | Arm symptoms | 8.8 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale | Arm symptoms | 8.3 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale | Systemic side-effects | 3.3 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale | Breast symptoms | 11.5 months |
Comparison: This Statistical Analysis corresponds to Systemic side-effects scalep-value: 0.02995% CI: [0.64, 0.98]Regression, Cox
Comparison: This Statistical Analysis corresponds to Breast symptoms scalep-value: 0.57195% CI: [0.71, 1.21]Regression, Cox
Comparison: This Statistical Analysis corresponds to Arm symptoms scalep-value: 0.18795% CI: [0.66, 1.09]Regression, Cox
Secondary
Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale
Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration. Deterioration is defined as a change from baseline ≥ minimally important difference (MID) as a change from baseline ≤ -MID for EORTC QLQ-C30 functional scales, global health status/QOL score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Role functioning | 8.3 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Global health status/quality of life | 8.3 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Physical functioning | 5.6 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Emotional functioning | 8.5 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Cognitive functioning | 11.1 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Social functioning | 8.8 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Cognitive functioning | 6.6 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Emotional functioning | 11.1 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Global health status/quality of life | 5.3 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Social functioning | 4.4 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Physical functioning | 2.8 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale | Role functioning | 4.2 months |
Comparison: This statistical Analysis corresponds to Global health status/quality of life scalep-value: 0.00395% CI: [0.55, 0.89]Regression, Cox
Comparison: This statistical Analysis corresponds to Physical functioning scalep-value: <0.00195% CI: [0.5, 0.76]Regression, Cox
Comparison: This statistical Analysis corresponds to Role functioning scalep-value: <0.00195% CI: [0.51, 0.79]Regression, Cox
Comparison: This statistical Analysis corresponds to Emotional functioning scalep-value: 0.81895% CI: [0.76, 1.25]Regression, Cox
Comparison: This statistical Analysis corresponds to Cognitive functioning scalep-value: 0.00495% CI: [0.54, 0.89]Regression, Cox
Comparison: This Statistical Analysis corresponds to Social functioning scalep-value: <0.00195% CI: [0.49, 0.78]Regression, Cox
Secondary
Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale
Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration. Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for EORTC QLQ-C30 symptom scores. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1. 999 means value not estimated.
Time frame: Assessed at Baseline, cycles 3, 5, 7, and then at every 3 cycles until the end of treatment, and at the visit after treatment, an average of 8 months.
Population: QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more). NA (Not Available): the statistical program has not been able to estimate the upper limit of the interval because of the lower number of participants answering the applicable questions.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Nausea and vomiting | 17.3 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Appetite loss | 17.4 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Dyspnea | 14.8 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Constipation | 12.4 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Pain | 6.2 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Diarrhea | 28.1 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Insomnia | 14.8 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Financial difficulties | 25.2 months |
| Cohort 1: Palbociclib Plus Exemestane | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Fatigue | 3.9 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Financial difficulties | 19.1 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Fatigue | 2.8 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Nausea and vomiting | 10 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Pain | 6.2 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Dyspnea | 17.8 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Insomnia | 10.7 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Appetite loss | 9.6 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Constipation | 16.3 months |
| Cohort 1: Capecitabine | Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale | Diarrhea | 4.9 months |
Comparison: This Statistical Analysis corresponds to Fatigue scalep-value: 0.00195% CI: [0.57, 0.86]Regression, Cox
Comparison: This Statistical Analysis corresponds to Nausea and vomiting scalep-value: <0.00195% CI: [0.45, 0.76]Regression, Cox
Comparison: This Statistical Analysis corresponds to Pain scalep-value: 0.04295% CI: [0.62, 0.99]Regression, Cox
Comparison: This Statistical Analysis corresponds to Dyspnea scalep-value: 0.59995% CI: [0.81, 1.44]Regression, Cox
Comparison: This Statistical Analysis corresponds to Insomnia scalep-value: 0.19695% CI: [0.64, 1.1]Regression, Cox
Comparison: This Statistical Analysis corresponds to Appetite loss scalep-value: 0.01195% CI: [0.54, 0.92]Regression, Cox
Comparison: This Statistical Analysis corresponds to Constipation scalep-value: 0.56495% CI: [0.83, 1.41]Regression, Cox
Comparison: This Statistical Analysis corresponds to Diarrhea scalep-value: <0.00195% CI: [0.32, 0.55]Regression, Cox
Comparison: This Statistical Analysis corresponds to Financial difficulties scalep-value: 0.11895% CI: [0.56, 1.07]Regression, Cox