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Phase III Study of Palbociclib (PD-0332991) in Combination With Endocrine Therapy (Exemestane or Fulvestrant) Versus Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative Metastatic Breast Cancer (MBC) Patients With Resistance to Aromatase Inhibitors (PEARL)

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ClinicalTrials.gov Identifier: NCT02028507
Recruitment Status : Active, not recruiting
First Posted : January 7, 2014
Last Update Posted : September 6, 2018
Sponsor:
Collaborators:
Pfizer
AstraZeneca
Information provided by (Responsible Party):
Spanish Breast Cancer Research Group

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 NSAI (letrozole or anastrozole) in cohort 1 or pevious 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.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Drug: Palbociclib Drug: Capecitabine Drug: Exemestane Drug: Fulvestrant Phase 3

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  (Clinical Trial)
Estimated Enrollment : 596 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Study of Palbociclib (PD-0332991) in Combination With Endocrine Therapy (Exemestane or Fulvestrant) Versus Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative Metastatic Breast Cancer (MBC) Patients With Resistance to Aromatase Inhibitors
Study Start Date : March 2014
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
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.
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.
Drug: Capecitabine



Primary Outcome Measures :
  1. Progression-Free Survival (PFS) based on the investigator's assessment [ Time Frame: Approximately Septiembre 2019 ]

    2 co-primary objetives:

    • To demonstrate that palbociclib in combination with fulvestrant is superior to capecitabine in prolonging Progression-Free Survival (PFS) regardless of the ESR1 mutational status.
    • To demonstrate that palbociclib in combination with endocrine therapy (exemestane or fulvestrant) is superior to capecitabine in prolonging PFS with estrogen receptor (ESR1) mutational status as wild type at study entry.


Secondary Outcome Measures :
  1. Objective Response: Complete Response (CR) plus Partial Response (PR) divided by the number of patients randomized with measurable disease [ Time Frame: Approximately September 2019 ]
  2. Clinical Benefit: CR plus PR plus stable disease lasting more than 24 weeks divided by all randomized patients (ITT population). [ Time Frame: Approximately September 2019 ]
  3. Response Duration (RD) (RD) [ Time Frame: Approximately September 2019 ]
  4. Overall Survival (OS). [ Time Frame: Approximately July 2020 ]
  5. 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.


Other Outcome Measures:
  1. 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 ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 whosedisease 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 immediatly 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 IHC for ER and/or 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/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 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, epirubicine 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02028507


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

Responsible Party: Spanish Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT02028507     History of Changes
Other Study ID Numbers: GEICAM/2013-02
2013-003170-27 ( EudraCT Number )
First Posted: January 7, 2014    Key Record Dates
Last Update Posted: September 6, 2018
Last Verified: September 2018

Keywords provided by Spanish Breast Cancer Research Group:
Palbociclib
Capecitabine
Hormonal Receptor positive
HER2 negative
Metastatic Breast Cancer
Resistance to non-steroidal Aromatase inhibitors
Fulvestrant
Exemestane
Aromatase inhibitor

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Capecitabine
Fulvestrant
Palbociclib
Exemestane
Estradiol
Aromatase Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Estrogens
Hormones
Protein Kinase Inhibitors
Enzyme Inhibitors
Steroid Synthesis Inhibitors