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Trial record 1 of 1 for:    NCT02028507
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Phase III Palbociclib With Endocrine Therapy vs. Capecitabine in HR+/HER2- MBC With Resistance to Aromatase Inhibitors (PEARL)

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ClinicalTrials.gov Identifier: NCT02028507
Recruitment Status : Completed
First Posted : January 7, 2014
Last Update Posted : January 20, 2021
Sponsor:
Collaborators:
Pfizer
AstraZeneca
Information provided by (Responsible Party):
Spanish Breast Cancer Research Group

Tracking Information
First Submitted Date  ICMJE January 2, 2014
First Posted Date  ICMJE January 7, 2014
Last Update Posted Date January 20, 2021
Actual Study Start Date  ICMJE March 13, 2014
Actual Primary Completion Date January 14, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2019)
Progression-Free Survival (PFS) [ Time Frame: Approximately September 2019 ]
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 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 3, 2014)
Progression-Free Survival (PFS). [ Time Frame: Approximately 36 months from the start of study randomization ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2019)
  • Objective Response (OR) [ Time Frame: Approximately September 2019 ]
    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 (CB) [ Time Frame: Approximately September 2019 ]
    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)
  • Response Duration (RD) (RD) [ Time Frame: Approximately September 2019 ]
    RD is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documented progressive disease using RECIST version 1.1 and based on the investigator's assessment, or to death due to any cause, whichever occurs first.
  • Overall Survival (OS) [ Time Frame: Approximately July 2020 ]
    OS is defined as the time from the date of randomization to the date of death from any cause.
  • The Number of Participants Who Experienced Adverse Events (AE) [ Time Frame: Day 1 of each cycle. ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 3, 2014)
  • Objective Response Rate (ORR): Complete Response (CR) plus Partial Response (PR) divided by the number of patients randomized with measurable disease [ Time Frame: Approximately 36 months from the start of study randomization ]
  • Clinical Benefit Rate (CBR): CR plus PR plus stable disease lasting more than 24 weeks divided by all randomized patients (ITT population). [ Time Frame: Approximately 36 months from the start of study randomization ]
  • Response Duration (RD) (RD) [ Time Frame: Approximately 36 months from the start of study randomization ]
  • Overall Survival (OS). [ Time Frame: Approximately 36 months from the start of study randomization ]
  • 1 year and 2 year survival probabilities [ Time Frame: 1 year and 2 year after patient inclusion at the trial ]
  • Safety [ Time Frame: Day 1 of each cycle. ]
    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.
Current Other Pre-specified Outcome Measures
 (submitted: December 12, 2019)
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). [ Time Frame: Approximately September 2019 ]
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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase III Palbociclib With Endocrine Therapy vs. Capecitabine in HR+/HER2- MBC With Resistance to Aromatase Inhibitors
Official Title  ICMJE 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
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Breast Cancer
Intervention  ICMJE
  • Drug: Palbociclib
    Other Name: Ibrance
  • Drug: Capecitabine
    Other Name: Xeloda
  • Drug: Exemestane
    Other Name: aromasil
  • Drug: Fulvestrant
    Other Name: faslodex
Study Arms  ICMJE
  • Experimental: Palbociclib plus Exemestane or Fulvestrant

    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

    • Cohort 1: Exemestane 25 mg orally once daily.
    • Cohort 2: Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.
    Interventions:
    • Drug: Palbociclib
    • Drug: Exemestane
    • Drug: Fulvestrant
  • Active Comparator: Capecitabine
    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.
    Intervention: Drug: Capecitabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 18, 2021)
693
Original Estimated Enrollment  ICMJE
 (submitted: January 3, 2014)
348
Actual Study Completion Date  ICMJE January 11, 2021
Actual Primary Completion Date January 14, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 [DIC], 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Hungary,   Israel,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02028507
Other Study ID Numbers  ICMJE GEICAM/2013-02
2013-003170-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Spanish Breast Cancer Research Group
Study Sponsor  ICMJE Spanish Breast Cancer Research Group
Collaborators  ICMJE
  • Pfizer
  • AstraZeneca
Investigators  ICMJE
Study Director: Study Director IiSGM, Universidad Complutense de Madrid, Madrid, Spain.
PRS Account Spanish Breast Cancer Research Group
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP