A randomised double blind placebo controlled phase II study of fulvestrant with or without the addition of vandetanib as treatment for patients with metastatic breast cancer resistant to aromatase inhibitor therapy.

For patients with advanced breast cancer that has spread around the body, hormone therapy is often the best treatment. As well as being very effective, this means that patients do not experience the toxicity and inconvenience of chemotherapy. However, eventually the cancer is likely to become resistant to hormone therapy and in this situation, although other hormone drugs can be used, they sometimes do not work very well. So it is important to find ways of getting the cancer to respond to hormone treatment again.

There are many different ways in which breast cancer cells become resistant to hormone treatments, including a 'signalling' pathway in the cells called RET [Receptor tyrosine kinase RET] REarranged during Transfection. Research has shown increased activity of RET signalling pathways in hormone resistant cancer cells.

Vandetanib is an oral drug that inhibits RET signalling in cells and has been shown in laboratory studies to prevent the growth of breast cancer cells which have become resistant to hormone therapy. Hormone therapy drugs include tamoxifen, and the aromatase inhibitors (anastrozole, letrozole and exemestane). The investigators therefore believe that giving vandetanib together with hormone therapy may help prevent resistance to treatment in patients with breast cancer. In this trial the investigators will combine this drug with fulvestrant, another hormone therapy drug which is sometimes used alone in patients who have developed resistance to aromatase inhibitors, or tamoxifen. So patients entering the trial will have one drug, fulvestrant, which is known to work and may also be given the experimental drug, vandetanib.

To properly determine if vandetanib works as the investigators believe, this study will compare the activity of vandetanib combined with fulvestrant with fulvestrant combined with an inactive, 'placebo' tablet in a group of patients for whom treatment with single agent fulvestrant is thought appropriate. The investigators plan to recruit a total of 160 patients. Half of them will be given fulvestrant and vandetanib and half will be given fulvestrant and placebo, and the treatment a particular patient will get will be chosen by random chance. Neither the patient nor the patients doctor will know whether the patient is getting vandetanib or the inactive placebo. The most important measure of effect will be the time until the cancer grows again, but the study will also look closely at the side effects of the drugs. The investigators will also look at whether the way in which an individual responds relates to the results from laboratory studies on the RET pathways carried out on previously stored tumour samples. This will mean that patients will not need to have additional biopsy samples taken.

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