Fulvestrant +/- Vandetanib in Advanced Aromatase Inhibitor Resistant Breast Cancer

Inclusion criteria: 1. Female ≥ 18 years 2. Post-menopausal 3. Minimum life expectancy 12 weeks 4. Histological confirmation of ER+ve breast cancer on primary tumour at diagnosis/on biopsy of metastasis 5. Histological confirmation of HER2 negative breast cancer on primary tumour at diagnosis/on biopsy of a metastasis 6. Clinical or histological confirmation of metastatic or locally advanced disease not amenable to curative surgical resection 7. ECOG 0-2 with no deterioration over previous 2 weeks 8. Measurable or non-measurable disease 9. Adequate bone marrow and organ function 10. Progressive disease whilst receiving third generation aromatase inhibitor for locally advanced or metastatic BC or relapsed with metastatic disease whilst receiving third generation AI in adjuvant setting 11. Radiological or objective clinical evidence of recurrence or progression on or after last systemic therapy prior to enrolment 12. ≤3 prior lines of endocrine therapy for ABC 13. ≤ 1 line of cytotoxic chemotherapy for ABC 14. Suitable for further endocrine therapy 15. Availability of archival tumour sample or fresh biopsy 16. Informed consent 17. Normal cardiac function Exclusion criteria: 1. Previous treatment with fulvestrant or inhibitors of RET pathway 2. Last dose chemotherapy, immunotherapy targeted therapy, biological therapy or tumour embolisation \<21 days (\<6 weeks for nitrosurea or mitomycin C) prior to study treatment 3. Last dose of palliative radiotherapy \<7 days prior to study treatment 4. Rapidly progressive visceral disease not suitable for further endocrine therapy 5. Spinal cord compression or brain/meningeal metastases unless asymptomatic, treated and stable and not requiring steroids for ≥ 4 weeks study treatment 6. Any of the following cardiac criteria: Significant cardiac event, superior vena cava syndrome, NYHA classification of heart disease ≥2 within 12 weeks before randomisation, or presence of cardiac disease that increases risk of ventricular arrhythmia; History of arrhythmia which is symptomatic or requires treatment, symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia; Congenital long QT syndrome; History of QT prolongation associated with other medications that required discontinuation of that medication; QTcB \>480msec on screening ECG 7. Electrolyte values: Potassium \<4.0 mmol/L despite supplementation, or above CTCAE Grade 1 upper limit, at randomisation; Magnesium below the normal range despite supplementation, or above CTCAE Grade 1 upper limit, at randomisation; Calcium (ionised or serum) below the normal range despite supplementation, or above Grade 1 upper limit, at randomisation 8. Creatinine clearance \<30 ml/min. Patients with creatinine clearance \<50 mL/min will start at a permanently reduced vandetanib dose of 200 mg. 9. Major surgery (excluding placement of vascular access) within 4 weeks before study treatment 10. Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and HIV 11. With the exception of alopecia, any unresolved toxicities from previous therapy greater than CTCAE grade 1 before study treatment 12. Elevated ALP in absence of bone metastasis 13. History of hypersensitivity to active or inactive excipients of vandetanib or fulvestrant 14. Evidence of dementia, altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent 15. Participation in another study with investigational product during last 30 days 16. Inability or unwillingness to comply with study procedures, including inability to take regular oral medication