ALERT: A Phase II Study of Alternating Eribulin and Hormonal Therapy in Pre-treated ER+ve Breast Cancer.

Study Overview
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Brief Summary
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A single centre, single arm phase II study of alternating eribulin and hormonal therapy in 12 patients with locally advanced or metastatic breast cancer who have received at least one hormonal therapy and at least one chemotherapy in the metastatic setting.

Detailed Description
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12 patients with locally advanced or metastatic breast cancer who have received at least one hormonal therapy and at least one chemotherapy in the metastatic setting will be enrolled to receive treatment. Once patients are consented and have completed on study screening, eribulin and Aromatase Inhibitor (AI) treatment will be alternated for up to 9 months, until disease progression or unacceptable toxicities, whichever is sooner. Patients will then attend a safety follow-up visit 4 weeks after completing treatment. Eribulin (Halaven®) is a non-taxane microtubule dynamics inhibitor. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into non-productive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. Eribulin is licenced for the treatment of patients with locally advanced or metastatic breast cancer who have previously received at least one chemotherapeutic regimen for the treatment of advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments. The aim of this study is to alternate eribulin and aromatase inhibitors, examining whether there may be breakthrough relapse during the AI therapy or on the other hand we can extend the duration that eribulin may be used for. Importantly, blood based biomarkers, the tumour derived fraction of circulating free DNA (cfDNA) termed circulating tumor DNA (ctDNA), and circulating tumour cells will be measured. A major aim of this study is to test whether biomarkers fluctuate between chemotherapy and AI treatment in the setting of advanced breast cancer.

Official Title
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ALERT: A Phase II Study of Alternating Eribulin and Hormonal Therapy in Pre-treated ER+ve Breast Cancer.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Eribulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Written informed consent prior to admission to this study 2. Aged 18≥over 3. Histologically confirmed ER+ve metastatic breast cancer according to local criteria 4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2 5. Have progressed after at least one hormonal therapy regime and at least one chemotherapy regime for advanced disease 6. Patients must have had prior treatment with an anthracycline and a taxane (either sequential or in combination) unless patients were not suitable for these treatments. This treatment can be in the adjuvant setting 7. Measurable sites of locally advanced and/or metastatic disease that can be accurately assessed by CT/MRI scan at baseline (RECIST v1.1)¹ 8. Life expectancy of ≥6 months 9. Adequate organ function, as defined by: Haemoglobin (Hb) ≥ 9 g/dL Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L Platelet count (Plts) ≥ 100 x 109/L White Blood Cell (WBC) ≥ 3.0 x 109/L Serum albumin ≤ 1.5 Upper Limit of Normal (ULN) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 x ULN if no demonstrable liver metastases or ≤ 5 x ULN in the presence of liver metastases. Alkaline Phosphatase Level (ALP) ≤ 5 x ULN Total bilirubin ≤ 1.5 x ULN if no demonstrable liver metastases or ≤ 3 x ULN in the presence of liver metastases Creatinine ≤ 1.5 x ULN or creatinine clearance >50ml/min 10. Postmenopausal as defined by age >50, no menstruation for >2 years, previous oophorectomy or lab results confirming this status 11. Premenopausal if has been subject to ovarian ablation/ suppression at least 3 weeks prior to commencing AI therapy RECIST v1.1 updated and now considers bone metastasis with an identifiable soft tissue mass to be measurable disease. Therefore, patients with bone metastasis are eligible, provided they have evaluable disease. Exclusion Criteria: 1.Triple negative or Human Epidermal Growth Factor Receptor 2 (HER2) positive cancer 2. Hypersensitivity to the active substance or to any of its excipients 3. History of another primary malignancy within 5 years prior to starting study treatment, except adequately treated basal or squamous cell carcinoma of the skin, carcinoma in site and the disease under study 4. Evidence of uncontrolled active infection 5. Severe hepatic impairment (Child-Pugh C) 6. Evidence of significant medical condition or laboratory finding which, in the opinion of the Investigator, makes it undesirable for the patient to participate in the trial 7. Concurrent therapy with any other investigational agent or everolimus 8. Concomitant use within 14 days prior to commencement of study treatment of any investigational agent 9. Uncontrolled abnormalities of serum potassium, sodium, calcium (corrected) phosphate or magnesium levels 10. Pregnant or lactating women. Effective non-hormonal contraception is mandatory for all patients of reproductive potential 11. Evidence of ovarian activity 12. Prior eribulin therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm study<br>3 x 3 weekly cycles at the recommended dose of eribulin as the ready to use solution, 1.23 mg/m2, administered intravenously over 2-5 minutes on days 1 and 8 of every 21 day cycle. This will then be followed by 9 weeks of AI treatment, to be followed again by 3 x 3 weekly cycles of eribulin and 9 weeks AI treatment. Patients will remain on treatment for up to 9 months, or until disease progression or unacceptable toxicities, whichever is sooner. | Drug: Eribulin<br> <br> * Other names: Halaven;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Kaplan-Meier Progression Free Survival as Assessed by RECIST v1.1 | Estimated Kaplan-Meier Progression free survival (PFS) to be defined as time from study entry to first evidence of disease progression or death due to any cause, as assessed by RECIST v1.0. | Fixed timepoints - 3, 6 and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate as Assessed by RECIST v1.1 | Clinical benefit rate (CBR), defined as the proportion of patients whose best overall response according to Response Evaluation Criteria in Solid Tumours (RECIST), v1.0 is either a complete response, partial response or stable disease for a least 6 months. | To be assessed at 3, 6 and 9 months. | 
| Safety and Tolerability | Safety and Tolerability were assessed by adverse events (AEs) and serious adverse events (SAEs) according the Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03. | Collected form consent to follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer