Phase III Palbociclib With Endocrine Therapy vs. Capecitabine in HR+/HER2- MBC With Resistance to Aromatase Inhibitors (PEARL)

Phase III Study of Palbociclib in Combination With Exemestane or Fulvestrant vs. Chemotherapy (Capecitabine) in Hormonal Receptor Positive/HER2 Negative Metastatic Breast Cancer Patients With Resistance to Aromatase Inhibitors

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Palbociclib; Drug: Capecitabine; Drug: Fulvestrant; Drug: Exemestane

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).

• Study Type: Interventional
• Enrollment (Actual): 693
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 5020
    • Universitätsklinik für Innere Medizin III
  • Steyr, Austria, 4400
    • Landes-Krankenhaus Steyr
  • Vienna, Austria, 1090
    • Universitätsklinik für Innere Medizin I
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem
  • Budapest, Hungary, 1122
    • National Institute of Oncology
  • Budapest, Hungary, 1115
    • Szent Imre Egyetemi Oktatokorhaz
  • Szeged, Hungary, 6720
    • Onkotherápiás Klinika
  • Szolnok, Hungary, 5004
    • Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelőintézet
• Israel
  • Kfar Saba, Israel, 44281
    • Meir Medical Center
  • Petah Tikva, Israel, 49100
    • Rabin Medical Center
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
  • Tel Hashomer, Israel, 52621
    • Sheba Medical Center
• Spain
  • A Coruña, Spain, 15006
    • Complejo Hospitalario Universitario A Coruña
  • A Coruña, Spain, 15009
    • Centro Oncologico de Galicia
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial
  • Barcelona, Spain, 08916
    • Hospital Universitario Germans Trias i Pujol
  • Caceres, Spain, 10003
    • Hospital San Pedro De Alcantara
  • Cordoba, Spain, 14004
    • Complejo Hospitalario Universitario Reina Sofía
  • Jaen, Spain, 23007
    • Complejo Hospitalario de Jaén
  • León, Spain, 24071
    • Hospital de Leon
  • Lleida, Spain, 25198
    • Hospital Universitario Arnau de Vilanova de Lleida
  • Lugo, Spain, 27003
    • Hospital Universitario Lucus Augusti
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28040
    • Hospital Clinico Universitario San Carlos
  • Madrid, Spain, 28021
    • Hospital Universitario 12 de Octubre
  • Malaga, Spain, 29010
    • Hospital Clínico Universitario Virgen de la Victoria
  • Murcia, Spain, 30120
    • Hospital Universitario Virgen de La Arrixaca
  • Salamanca, Spain, 37007
    • Hospital Clínico Universitario de Salamanca
  • San Sebastian, Spain, 20014
    • Hospital de Donostia
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Toledo, Spain, 45004
    • Hospital Virgen de la Salud
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
  • Zaragoza, Spain, 50009
    • Hospital Clínico Universitario de Zaragoza "Lozano Blesa"
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08908
      • ICO de L'Hospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Palbociclib; Other Names: Ibrance; Drug: Exemestane; Other Names: aromasil
Active Comparator: 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.	Drug: Capecitabine; Other Names: Xeloda
Experimental: 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.	Drug: Palbociclib; Other Names: Ibrance; Drug: Fulvestrant; Other Names: faslodex
Active Comparator: 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.	Drug: Capecitabine; Other Names: Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Through study treatment, and average of 8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization date to date of first documentation of progression or death (an average of 8 months)
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.	From randomization until death (up to approximately 34 months)
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.	Through study treatment, and average of 8 months
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.	Through study treatment, and average of 8 months
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	Through study treatment, and average of 8 months
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.	Through study treatment, and average of 8 months
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.	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.
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.	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.
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.	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.
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.	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.
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.	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.
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.	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.
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.	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 (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.	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 (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.	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 (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.	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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Outcomes: biomarkers related to breast tumor sensitivity and/or resistance to palbociclib (e.g., Ki67, p16/CDKN2A, pRb, CyclinD and others) or breast cancer (e.g. PTEN, ERBB2, BRCA 1 and BRCA2).	Baseline biomarker values from most recently obtained tumor tissue (deeply recommended from metastatic tumor) will be used for central assessment of biomarkers related to breast tumor sensitivity and/or resistance to palbociclib (e.g., Ki67, p16/CDKN2A, pRb, CyclinD and others) or breast cancer (e.g. PTEN, ERBB2, BRCA1 and BRCA2). A whole blood sample will be collected for potential pharmacogenomic analyses related to drug response or adverse drug reactions. For example, putative safety biomarkers, drug metabolizing enzyme genes, drug transport protein genes, or genes thought to be related to the drug mechanism of action may be examined. Correlative plasma samples will be collected for exploratory analysis to analyze the pharmacodynamic (PD) treatment effects on circulating free DNA or RNA and explore specific breast cancer and efficacy predictive biomarkers (e.g. PIK3CA mutation). Sample will be collected from all patients, unless prohibited by local regulations.	Approximately September 2019

Collaborators and Investigators

• Sponsor: Spanish Breast Cancer Research Group
• Collaborators: Pfizer; AstraZeneca
• Investigators: Study Director: Study Director, IiSGM, Universidad Complutense de Madrid, Madrid, Spain.

Publications and helpful links

General Publications

• Martin M, Zielinski C, Ruiz-Borrego M, Carrasco E, Turner N, Ciruelos EM, Munoz M, Bermejo B, Margeli M, Anton A, Kahan Z, Csoszi T, Casas MI, Murillo L, Morales S, Alba E, Gal-Yam E, Guerrero-Zotano A, Calvo L, de la Haba-Rodriguez J, Ramos M, Alvarez I, Garcia-Palomo A, Huang Bartlett C, Koehler M, Caballero R, Corsaro M, Huang X, Garcia-Saenz JA, Chacon JI, Swift C, Thallinger C, Gil-Gil M. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol. 2021 Apr;32(4):488-499. doi: 10.1016/j.annonc.2020.12.013. Epub 2020 Dec 29.
• Martin M, Zielinski C, Ruiz-Borrego M, Carrasco E, Ciruelos EM, Munoz M, Bermejo B, Margeli M, Csoszi T, Anton A, Turner N, Casas MI, Morales S, Alba E, Calvo L, de la Haba-Rodriguez J, Ramos M, Murillo L, Santaballa A, Alonso-Romero JL, Sanchez-Rovira P, Corsaro M, Huang X, Thallinger C, Kahan Z, Gil-Gil M. Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study. Eur J Cancer. 2022 Jun;168:12-24. doi: 10.1016/j.ejca.2022.03.006. Epub 2022 Apr 13.
• Kahan Z, Gil-Gil M, Ruiz-Borrego M, Carrasco E, Ciruelos E, Munoz M, Bermejo B, Margeli M, Anton A, Casas M, Csoszi T, Murillo L, Morales S, Calvo L, Lang I, Alba E, de la Haba-Rodriguez J, Ramos M, Lopez IA, Gal-Yam E, Garcia-Palomo A, Alvarez E, Gonzalez-Santiago S, Rodriguez CA, Servitja S, Corsaro M, Rodrigalvarez G, Zielinski C, Martin M. Health-related quality of life with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive metastatic breast cancer: Patient-reported outcomes in the PEARL study. Eur J Cancer. 2021 Oct;156:70-82. doi: 10.1016/j.ejca.2021.07.004. Epub 2021 Aug 20.
• Guerrero-Zotano A, Belli S, Zielinski C, Gil-Gil M, Fernandez-Serra A, Ruiz-Borrego M, Ciruelos Gil EM, Pascual J, Munoz-Mateu M, Bermejo B, Margeli Vila M, Anton A, Murillo L, Nissenbaum B, Liu Y, Herranz J, Fernandez-Garcia D, Caballero R, Lopez-Guerrero JA, Bianco R, Formisano L, Turner N, Martin M. CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer. Clin Cancer Res. 2023 Apr 14;29(8):1557-1568. doi: 10.1158/1078-0432.CCR-22-2206.

Helpful Links

• GEICAM is a Spanish Breast Cancer Research Group

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2014
• Primary Completion (Actual): January 14, 2019
• Study Completion (Actual): January 11, 2021

Study Registration Dates

• First Submitted: January 2, 2014
• First Submitted That Met QC Criteria: January 3, 2014
• First Posted (Estimated): January 7, 2014

Study Record Updates

• Last Update Posted (Actual): September 25, 2024
• Last Update Submitted That Met QC Criteria: September 23, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Capecitabine; HER2 negative; Metastatic Breast Cancer; Exemestane; Fulvestrant; Aromatase inhibitor; Palbociclib; Hormonal Receptor positive; Resistance to non-steroidal Aromatase inhibitors
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Capecitabine; Fulvestrant; Palbociclib; Exemestane
• Other Study ID Numbers: GEICAM/2013-02; 2013-003170-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO