Clinical trial NCT02028507: Phase III Palbociclib With Endocrine Therapy vs. Capecitabine in HR+/HER2- MBC With Resistance to Aromatase Inhibitors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Spanish Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Pfizer
name: AstraZeneca
First posted: 2014-01-07
Enrollment: 693
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility 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 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

Primary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Through study treatment, and average of 8 months
Secondary outcomes:
measure: PFS Estrogen Receptor 1 (ESR1) Wild Type
timeFrame: From randomization date to date of first documentation of progression or death (an average of 8 months)
measure: Overall Survival (OS) ESR1 Wild Type
timeFrame: From randomization until death (up to approximately 34 months)
measure: Objective Response Rate (ORR) ESR1 Wild Type
timeFrame: Through study treatment, and average of 8 months
measure: Clinical Benefit Rate (CBR) ESR1 Wild Type
timeFrame: Through study treatment, and average of 8 months
measure: Response Duration (RD) ESR1 Wild Type
timeFrame: Through study treatment, and average of 8 months
measure: The Number of Participants Who Experienced Adverse Events (AE)
timeFrame: Through study treatment, and average of 8 months
measure: 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
timeFrame: 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.
measure: Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores
timeFrame: 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.
measure: Overall Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores
timeFrame: 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.
measure: Overall Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale
timeFrame: 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.
measure: Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale
timeFrame: 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.
measure: Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale
timeFrame: 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.
measure: Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale
timeFrame: 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.
measure: Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale
timeFrame: 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 outcomes:
Locations:
city: Salzburg
country: Austria
facility: Universitätsklinik für Innere Medizin III
city: Steyr
country: Austria
facility: Landes-Krankenhaus Steyr
city: Vienna
country: Austria
facility: Universitätsklinik für Innere Medizin I
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Szent Imre Egyetemi Oktatókórház
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Szeged
country: Hungary
facility: Onkotherápiás Klinika
city: Szolnok
country: Hungary
facility: Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelőintézet
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Tel Hashomer
country: Israel
facility: Sheba Medical Center
city: L'Hospitalet de Llobregat
country: Spain
facility: ICO de L'Hospitalet
state: Barcelona
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: A Coruña
country: Spain
facility: Centro Oncológico de Galicia
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Barcelona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
city: Caceres
country: Spain
facility: Hospital San Pedro De Alcántara
city: Cordoba
country: Spain
facility: Complejo Hospitalario Universitario Reina Sofía
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaén
city: León
country: Spain
facility: Hospital de León
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova de Lleida
city: Lugo
country: Spain
facility: Hospital Universitario Lucus Augusti
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Clínico Universitario San Carlos
city: Malaga
country: Spain
facility: Hospital Clínico Universitario Virgen de la Victoria
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Salamanca
country: Spain
facility: Hospital Clínico Universitario de Salamanca
city: San Sebastian
country: Spain
facility: Hospital de Donostia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Toledo
country: Spain
facility: Hospital Virgen de La Salud
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario de Zaragoza "Lozano Blesa"
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: IiSGM, Universidad Complutense de Madrid, Madrid, Spain.
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.