MedPath

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

Phase 3
Completed
Conditions
Metastatic Breast Cancer
Interventions
Registration Number
NCT02028507
Lead Sponsor
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 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).

Recruitment & Eligibility

Status
COMPLETED
Sex
Female
Target Recruitment
693
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.

Read More
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

Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Cohort 1: Palbociclib plus ExemestanePalbociclib- 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.
Cohort 1: Palbociclib plus ExemestaneExemestane- 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.
Cohort 1:CapecitabineCapecitabineCohort 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.
Cohort 2: Palbociclib plus FulvestrantFulvestrant- 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.
Cohort 2: Palbociclib plus FulvestrantPalbociclib- 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.
Cohort 2:CapecitabineCapecitabineCohort 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.
Primary Outcome Measures
NameTimeMethod
Progression-Free Survival (PFS)Through study treatment, and average of 8 months

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.

Secondary Outcome Measures
NameTimeMethod
PFS Estrogen Receptor 1 (ESR1) Wild TypeFrom randomization date to date of first documentation of progression or death (an average of 8 months)

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.

Overall Survival (OS) ESR1 Wild TypeFrom randomization until death (up to approximately 34 months)

OS is defined as the time from the date of randomization to the date of death from any cause.

Objective Response Rate (ORR) ESR1 Wild TypeThrough study treatment, and average of 8 months

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 Rate (CBR) ESR1 Wild TypeThrough study treatment, and average of 8 months

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.

Response Duration (RD) ESR1 Wild TypeThrough study treatment, and average of 8 months

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

The Number of Participants Who Experienced Adverse Events (AE)Through study treatment, and average of 8 months

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.

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 ScoresAssessed 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.

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.

Overall Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale ScoresAssessed 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.

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.

Overall Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale ScoresAssessed 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.

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.

Overall Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale ScoresAssessed 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.

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.

Overall Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index ScoresAssessed 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.

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.

Overall Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores ScaleAssessed 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.

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.

Time to Deterioration (TTD) in EORTC QLQ-C30 Functional ScaleAssessed 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 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.

Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom ScaleAssessed 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 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.

Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional ScaleAssessed 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 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.

Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom ScaleAssessed 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 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.

Trial Locations

Locations (37)

Sheba Medical Center

🇮🇱

Tel Hashomer, Israel

Universitätsklinik für Innere Medizin III

🇦🇹

Salzburg, Austria

Landes-Krankenhaus Steyr

🇦🇹

Steyr, Austria

Szent Imre Egyetemi Oktatókórház

🇭🇺

Budapest, Hungary

Hospital Clinic i Provincial

🇪🇸

Barcelona, Spain

Complejo Hospitalario Universitario A Coruña

🇪🇸

A Coruña, Spain

Semmelweis Egyetem

🇭🇺

Budapest, Hungary

Hospital del Mar

🇪🇸

Barcelona, Spain

Universitätsklinik für Innere Medizin I

🇦🇹

Vienna, Austria

Onkotherápiás Klinika

🇭🇺

Szeged, Hungary

National Institute of Oncology

🇭🇺

Budapest, Hungary

Tel Aviv Sourasky Medical Center

🇮🇱

Tel Aviv, Israel

Jász-Nagykun-Szolnok Megyei Hetényi Géza Kórház-Rendelőintézet

🇭🇺

Szolnok, Hungary

Meir Medical Center

🇮🇱

Kfar Saba, Israel

Rabin Medical Center

🇮🇱

Petah Tikva, Israel

ICO de L'Hospitalet

🇪🇸

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital San Pedro De Alcántara

🇪🇸

Caceres, Spain

Hospital Universitario Arnau de Vilanova de Lleida

🇪🇸

Lleida, Spain

Hospital General Universitario Gregorio Marañón

🇪🇸

Madrid, Spain

Hospital de Donostia

🇪🇸

San Sebastian, Spain

Hospital Clínico Universitario de Salamanca

🇪🇸

Salamanca, Spain

Hospital Clínico Universitario de Valencia

🇪🇸

Valencia, Spain

Hospital Universitario La Fe

🇪🇸

Valencia, Spain

Hospital Universitario Miguel Servet

🇪🇸

Zaragoza, Spain

Complejo Hospitalario de Jaén

🇪🇸

Jaen, Spain

Hospital de León

🇪🇸

León, Spain

Hospital Universitario 12 de Octubre

🇪🇸

Madrid, Spain

Hospital Clínico Universitario San Carlos

🇪🇸

Madrid, Spain

Centro Oncológico de Galicia

🇪🇸

A Coruña, Spain

Hospital Universitario Germans Trias i Pujol

🇪🇸

Barcelona, Spain

Complejo Hospitalario Universitario Reina Sofía

🇪🇸

Cordoba, Spain

Hospital Clínico Universitario Virgen de la Victoria

🇪🇸

Malaga, Spain

Hospital Universitario Lucus Augusti

🇪🇸

Lugo, Spain

Hospital Universitario Virgen de la Arrixaca

🇪🇸

Murcia, Spain

Hospital Universitario Virgen del Rocío

🇪🇸

Sevilla, Spain

Hospital Virgen de La Salud

🇪🇸

Toledo, Spain

Hospital Clínico Universitario de Zaragoza "Lozano Blesa"

🇪🇸

Zaragoza, Spain

© Copyright 2025. All Rights Reserved by MedPath