Fulvestrant +/- Vandetanib in Advanced Aromatase Inhibitor Resistant Breast Cancer
- Registration Number
- NCT02530411
- Lead Sponsor
- Velindre NHS Trust
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- Female
- Target Recruitment
- 160
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Experimental Fulvestrant Fulvestrant 500mg Intra Muscular (IM) Day 1 (D1), D15, then D1 of every 28 day cycle Vandetanib 300 mg Per os (po) daily Clinician review D1, D15, weeks 4, 8, 12, 16, 20, 24 then 12 weekly. Computerised Axial Tomography (CT) at week 8, 16, 24 then 12 weekly. Control Fulvestrant Fulvestrant 500mg IM D1, D15, then D1 of every 28 day cycle Placebo po daily Clinician review D1, D15, weeks 4, 8, 12, 16, 20, 24 then 12 weekly. CT at week 8, 16, 24 then 12 weekly. Experimental Vandetanib Fulvestrant 500mg Intra Muscular (IM) Day 1 (D1), D15, then D1 of every 28 day cycle Vandetanib 300 mg Per os (po) daily Clinician review D1, D15, weeks 4, 8, 12, 16, 20, 24 then 12 weekly. Computerised Axial Tomography (CT) at week 8, 16, 24 then 12 weekly.
- Primary Outcome Measures
Name Time Method Progression-Free Survival (PFS) Time to event. This outcome will be assessed over an estimated period of up to 45 months. Time to event based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. - Time from randomisation to any disease progression and/or death.
- Secondary Outcome Measures
Name Time Method Objective Response Rate Time to event. This outcome will be assessed when all participants have completed a minimum 12 months follow-up and at least 98 disease progression events are observed, i.e. over an estimated period of up to 45 months. Objective Response Rate as assessed by the Response Evaluation Criteria in Solid Tumours (RECIST). Disease progression will be formally assessed according to the RECIST v1.1 criteria.
Overall Survival Time to event. This outcome will be assessed over an estimated period of up to 45 months. Time from enrolment to death from any cause with those still alive censored at date last seen.
Exploratory analysis: The influence of RET signalling pathway components expression on vandetanib activity. Data will be analysed when archival tumour tissue samples have been collected from all consenting patients. This outcome will be assessed and data presented up to 45 months. The influence of RET signalling pathway components expression on vandetanib activity.
Safety and tolerability of the fulvestrant/vandetanib trial drug regime measured by the number of participants with reported serious adverse events (composite outcome measure). Initial safety reviews will be conducted after 20 and 40 patients have completed at least one cycle of treatment (estimated 8 and 16 months after enrolment of the first patient respectively). Final assessment/data presentation by 2018 (up to 45 months). This outcome will observe the number of side effects of the combined vandetanib and fulvestrant drug regime as recorded via real-time serious adverse event reporting.
Feasibility of use of the combined vandetanib/fulvestrant trial drug regime measured by the number of participants requiring dose delays, reductions and/or study withdrawal to manage reported serious adverse events. Initial safety reviews will be conducted after 20 and 40 patients have completed at least one cycle of treatment (estimated 8 and 16 months after enrolment of the first patient respectively). Final assessment/data presentation by 2018 (up to 45 months). This outcome will assess the number of patients requiring dose delays, reductions, and/or study withdrawal to manage side effects recorded via real-time serious adverse event reporting.
Clinical Benefit Rate (measuring the proportion of patients with no disease progression after six months of treatment) The trial data will be analysed when all participants have completed a minimum 12 months follow-up and at least 98 disease progression events are observed. This outcome will be assessed and the data presented up to 45 months. The clinical benefit rate will be assessed by measuring the proportion of patients with no disease progression after six months of treatment. Disease progression will be formally assessed according to the RECIST v1.1 criteria.
Trial Locations
- Locations (5)
Royal Bournemouth Hospital
🇬🇧Bournemouth, Dorset, United Kingdom
Velindre Cancer Center, Velindre Hospital
🇬🇧Cardiff, Wales, United Kingdom
Royal United Hospital Bath
🇬🇧Bath, United Kingdom
Royal Devon and Exeter Hospital
🇬🇧Exeter, England, United Kingdom
Royal Cornwall Hospital
🇬🇧Truro, Cornwall, England, United Kingdom