Metastatic breast cancer Cancer Metastatic breast cancer
Conditions
Interventions
Participants are randomly allocated to one of two study arms. Participants in both arms will receive up to 16 x 28 day cycles of treatment over a total duration of 64 weeks.
Intervention arm: Partic
Sponsors
Velindre NHS Trust
Eligibility
Sex/Gender
Female
Inclusion criteria
Inclusion criteria: 1. Adult female patients aged 18 years or over 2. Post-menopausal patients. Post-menopausal can be defined as either of the following criteria: 2.1. Amenorrhoeic throughout AND after therapy with a third generation AI, without a GnRH analogue (eg. goserelin) AND screening FSH and estradiol in institutional post-menopausal ranges OR 2.2. Treatment of early or metastatic breast cancer with a third generation AI and GnRH analogue, with discontinuation of the GnRH analogue for at least 6 months AND no resumption of menstruation AND screening FSH and estradiol in institutional postmenopausal ranges 3. Minimum life expectancy of 12 weeks 4. Histological confirmation of ER+ve breast cancer on primary tumour at diagnosis or on biopsy of a metastasis. ER is considered positive if =10% of tumour cells stain positive for ER (whatever the intensity of staining). If no percentage score is available then a Quick (Allred) Score of =4/8 will be considered ER positive 5. Histological confirmation of HER2 negative breast cancer on primary tumour at diagnosis or on biopsy of a metastasis. HER2 is considered negative by IHC if scored 0 or 1+ by Herceptest or similar assay. If HER2 is scored 2+ or 2+/3+ by IHC then HER2 gene amplification must be assessed by FISH/CISH/DDISH and the ratio of HER2 to EP17 probes must be 14 days prior to the determination of haemoglobin) 9.4. Prothrombin time (seconds) INR= 1.5 x ULN 9.5. Potassium, calcium (corrected for serum albumin) and magnesium within normal limits (WNL) for the institution 9.6. Serum creatinine = 1.5xULN 9.7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5xULN (or < 5.0 x ULN if liver metastases are present) 9.8. Total bilirubin =1.5 times ULN 10. Progressive disease whilst receiving a third generation aromatase inhibitor (exemestane, anastrazole or letrozole) for locally advanced or metastatic BC or relapsed with metastatic disease whilst receiving a third generation AI in the adjuvant setting. The AI does not need to be the last treatment immediately prior to recruitment 11. Radiological or objective clinical evidence of recurrence or progression on or after the last systemic therapy prior to enrollment 12. No more than 3 prior lines of endocrine therapy for ABC. If an attempt to downstage a locally advanced tumour with endocrine therapy was made in the absence of MBC, and the tumour operated upon, then this does not count as a line of therapy for ABC. In contrast, if the tumour remained inoperable then this treatment should be included as a line of therapy for ABC 13. No more than 1 line of cytotoxic chemotherapy for ABC (see inclusion criterion 11 12 for note on definition of lines of therapy) 14. Suitable for further endocrine therapy according to the treating clinician 15. Availability of archival tumour sample or fresh biopsy for exploratory analysis 16. Provision of informed consent prior to any study specific procedures 17. Normal cardiac function
Exclusion criteria
Exclusion criteria: 1. Previous treatment with fulvestrant or inhibitors of the RET pathway 2. Last dose chemotherapy, immunotherapy targeted therapy, biological therapy or tumour embolisation less than 21days (less than 6 weeks for nitrosurea or mitomycin C) prior to the first dose of study treatment. Note: endocrine (hormone) therapy is not considered a targeted or biological therapy for the purposes of this study. Denosumab and bisphosphonate treatment are accepted concomitant medications as long as they are started at least 14 days prior to study drug commencement. 3. Last dose of palliative radiotherapy less than 7 days prior to the first dose of 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 at least 4 weeks before starting study treatment 6. Any of the following cardiac criteria: 6.1. Significant cardiac event (e.g., myocardial infarction), superior vena cava syndrome, New York Heart Association (NYHA) classification of heart disease =2 within 12 weeks before randomisation (see Appendix 2), or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia 6.2. History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE v 4.03 Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted. 6.3. Congenital long QT syndrome 6.4. History of QT prolongation associated with other medications that required discontinuation of that medication 6.5. QTcB >480msec on screening ECG (Note: The screening ECG must be repeated three times 5 minutes apart. The average QTc from the three screening ECGs must be = 480 ms in order for the patient to be eligible for the study). If the average QTc is >480ms, the ECGs may be repeated at least 24 hours later, and the average must be =480 ms 7. Patients with the following electrolyte values (the rational is due to the increased risk of prolonged QTc): 7.1. Potassium <4.0 mmol/L despite supplementation, or above the CTCAE Grade 1 upper limit, at the time of randomisation 7.2. Magnesium below the normal range despite supplementation, or above the CTCAE Grade 1 upper limit, at the time of randomisation 7.3. Calcium (ionised or serum) below the normal range despite supplementation, or above the Grade 1 upper limit, at the time of randomisation. If serum calcium is used, correction should be applied to account for hypoalbuminemia, if present, where the corrected serum calcium (mg/dL) is equal to measured serum Ca (mg/dL) + 0.8 x (4 serum albumin g/dL) 8. Creatinine clearance <30 ml/min (calculated by CockcroftGault formula, see Appendix 4). 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 the first dose of study treatment 10. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. 11. With t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Progression-free survival is assessed using RECIST V1.1 criteria over an estimated period of up to 45 months. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Clinical Benefit Rate (proportion patients with no disease progression after 6 months treatment) is measured when all participants have completed a minimum 12 months follow-up 2. Influence of RET signalling pathway expression on vandetanib activity is analysed when archival tumour tissue samples have been collected from all consenting patients 3. Feasibility of use of the trial drug regime measured by dose delays/reductions and withdrawals after 20 and 40 patients have completed at least one cycle of treatment 4. Objective Response Rate is determined by measuring disease progression assessed via RECIST V1.1 when all participants have completed a minimum 12 month follow up 5. Overall Survival is assessed over an estimated period of up to 45 months 6. Safety and tolerability of the trial drug regime is measured by SAEs (composite outcome measure) after 20 and 40 patients have completed at least one cycle of treatment | — |
Countries
England, Scotland, United Kingdom, Wales
Contacts
Public ContactMargherita Carucci
Outcome results
None listed