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

NCT02028507 | Completed Phase 3 Results DMC

• 2 other identifiers: GEICAM/2013-022013-003170-27
• Study Type: interventional
• Target: 693
• Locations: 4 countries
• Sites: 37

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.

Conditions

Metastatic Breast Cancer

Keywords

Palbociclib; Capecitabine; Hormonal Receptor positive; HER2 negative; Metastatic Breast Cancer; Resistance to non-steroidal Aromatase inhibitors; Fulvestrant; Exemestane; Aromatase inhibitor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• PFS Estrogen Receptor 1 (ESR1) Wild Type

  From randomization date to date of first documentation of progression or death (an average of 8 months)

• Overall Survival (OS) ESR1 Wild Type

  From randomization until death (up to approximately 34 months)

• Objective Response Rate (ORR) ESR1 Wild Type

  Through study treatment, and average of 8 months

• Clinical Benefit Rate (CBR) ESR1 Wild Type

  Through study treatment, and average of 8 months

• Response Duration (RD) ESR1 Wild Type

  Through study treatment, and average of 8 months

Study Arms (4)

Cohort 1: Palbociclib plus Exemestane

EXPERIMENTAL

\- 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; Drug: Exemestane

Cohort 1:Capecitabine

ACTIVE COMPARATOR

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

Cohort 2: Palbociclib plus Fulvestrant

EXPERIMENTAL

\- 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; Drug: Fulvestrant

Cohort 2:Capecitabine

ACTIVE COMPARATOR

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

Interventions

Palbociclib DRUG

Also known as: Ibrance

Cohort 1: Palbociclib plus Exemestane; Cohort 2: Palbociclib plus Fulvestrant

Capecitabine DRUG

Also known as: Xeloda

Cohort 1:Capecitabine; Cohort 2:Capecitabine

Exemestane DRUG

Also known as: aromasil

Cohort 1: Palbociclib plus Exemestane

Fulvestrant DRUG

Also known as: faslodex

Cohort 2: Palbociclib plus Fulvestrant

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient has signed the informed consent document.
• 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.
• 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).
• 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.
• 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).
• 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.
• 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.
• Patient is at least 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) Performance Status minor or equal to 1.
• Life expectancy major or equal to 12 weeks.
• Adequate organ and bone marrow function.
• 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
• 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).

You may not qualify if:

• 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.
• 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).
• 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.
• 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.
• 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.
• 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
• Patients who received before randomization:
• Any investigational agent within 4 weeks

Sponsors & Collaborators

• Spanish Breast Cancer Research Group: lead
• Pfizer: collaborator
• AstraZeneca: collaborator

Study Sites (37)

Universitätsklinik für Innere Medizin III

Salzburg, 5020, Austria

Location

Landes-Krankenhaus Steyr

Steyr, 4400, Austria

Location

Universitätsklinik für Innere Medizin I

Vienna, 1090, Austria

Location

Semmelweis Egyetem

Budapest, 1083, Hungary

Location

Szent Imre Egyetemi Oktatókórház

Budapest, 1115, Hungary

Location

National Institute of Oncology

Budapest, 1122, Hungary

Location

Onkotherápiás Klinika

Szeged, 6720, Hungary

Location

Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelőintézet

Szolnok, 5004, Hungary

Location

Meir Medical Center

Kfar Saba, 44281, Israel

Location

Rabin Medical Center

Petah Tikva, 49100, Israel

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 64239, Israel

Location

Sheba Medical Center

Tel Litwinsky, 52621, Israel

Location

ICO de L'Hospitalet

L'Hospitalet de Llobregat, Barcelona, 08908, Spain

Location

Complejo Hospitalario Universitario A Coruña

A Coruña, 15006, Spain

Location

Centro Oncológico de Galicia

A Coruña, 15009, Spain

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Clinic i Provincial

Barcelona, 08036, Spain

Location

Hospital Universitario Germans Trias i Pujol

Barcelona, 08916, Spain

Location

Hospital San Pedro De Alcántara

Cáceres, 10003, Spain

Location

Complejo Hospitalario Universitario Reina Sofía

Córdoba, 14004, Spain

Location

Hospital de Donostia

Donostia / San Sebastian, 20014, Spain

Location

Complejo Hospitalario de Jaén

Jaén, 23007, Spain

Location

Hospital de León

León, 24071, Spain

Location

Hospital Universitario Arnau de Vilanova de Lleida

Lleida, 25198, Spain

Location

Hospital Universitario Lucus Augusti

Lugo, 27003, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28021, Spain

Location

Hospital Clínico Universitario San Carlos

Madrid, 28040, Spain

Location

Hospital Clínico Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Universitario Virgen de la Arrixaca

Murcia, 30120, Spain

Location

Hospital Clínico Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

Hospital Virgen de La Salud

Toledo, 45004, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Universitario La Fe

Valencia, 46026, Spain

Location

Hospital Clínico Universitario de Zaragoza "Lozano Blesa"

Zaragoza, 50009, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

Location

Related Publications (4)

• 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.

  PMID: 33385521 RESULT

• 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.

  PMID: 35429901 RESULT

• 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.

  PMID: 34425406 RESULT

• 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.

  PMID: 36749874 RESULT

Related Links

• GEICAM is a Spanish Breast Cancer Research Group

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib; Capecitabine; exemestane; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and Caveats

Potential limitations of the study are: * capecitabine outcome was better than that initially anticipated (9 months compared with 6 months in the protocol assumptions) * open-label study design may lead to biased interpretations * the subtype classification for the exploratory objective was carried out in 70% of patients in the primary tumour, which might have changed in the metastatic disease in a proportion of patients

Results Point of Contact

• Title: Scientific Director / Medical Lead / Project Manager
• Organization: Spanish Breast Cancer Research Group

geicam@geicam.org

+34916592870

Study Officials

• Study Director

  IiSGM, Universidad Complutense de Madrid, Madrid, Spain.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 2, 2014
• First Posted: January 7, 2014
• Study Start: March 13, 2014
• Primary Completion: January 14, 2019
• Study Completion: January 11, 2021
• Last Updated: September 25, 2024
• Results First Posted: September 25, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

HU (5); AU (3); IL (4); ES (25)