| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic breast cancer that has become resistant to aromatase inhibitor therapy |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced breast cancer that has become resistant to hormone therapy |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To establish whether the combination of vandetanib and fulvestrant will improve clinical outcome in patients with endocrine resistant advanced breast cancer (RECIST v1.1). |
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| E.2.2 | Secondary objectives of the trial |
To determine whether the combination of vandetanib and fulvestrant is tolerable, safe and feasible to deliver.
To determine whether vandetanib activity is related to the activation status of the tumour RET signalling pathway.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients meeting all of the following criteria may be included in the trial:
1. Adult female patients, aged ≥ 18 years.
2. Post-menopausal patients. Post-menopausal can be defined as either of the following criteria:
a. 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
b. 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 post-menopausal 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/D-DISH and the ratio of HER2 to CEP17 probes must be <2.0.
6. Clinical or histological confirmation of metastatic or locally advanced disease not amenable to curative surgical resection.
7. ECOG performance status 0 to 2 with no deterioration over the previous 2 weeks.
8. Measurable or non-measurable disease.
9. Patient has adequate bone marrow and organ function as defined by the following:
a. Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L.
b. Platelets (plts) ≥ 100 x 109/L.
c. Haemoglobin (Hgb) ≥ 9 g/dl [Note: any blood transfusion must be >14 days prior to the determination of haemoglobin].
d. Prothrombin time (seconds) INR≤ 1.5 x ULN.
e. Potassium, calcium (corrected for serum albumin) and magnesium within normal limits (WNL) for the institution.
f. Serum creatinine ≤ 1.5xULN.
g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5xULN (or < 5.0 x ULN if liver metastases are present).
h. 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 enrolment.
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.
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| E.4 | Principal 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 21 days (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:
a. 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.
b. 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.
c. Congenital long QT syndrome.
d. History of QT prolongation associated with other medications that required discontinuation of that medication
e. 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):
a) Potassium <4.0 mmol/L despite supplementation, or above the CTCAE Grade 1 upper limit, at the time of randomisation.
b) Magnesium below the normal range despite supplementation, or above the CTCAE Grade 1 upper limit, at the time of randomisation.
c) 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 Cockcroft-Gault 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 the exception of alopecia, any unresolved toxicities from previous therapy greater than CTCAE grade 1 at the time of starting study treatment.
12. Elevated Alkaline phosphatase (ALP) in the absence of bone metastasis. If the patient has elevated ALP in the presence of bone metastasis and liver function is otherwise considered adequate in the investigator’s judgement, then the patient is not excluded.
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 clinical study with an investigational product (IP) during the last 30 days.
16. Inability or unwillingness to comply with study procedures, including the inability to take regular oral medication.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| To establish the anti-tumour activity of the combination of vandetanib with fulvestrant as measured by progression-free survival (PFS) compared with fulvestrant and placebo. This is the time from randomisation to any disease progression and/or any death, defined according to strict RECIST v1.1 criteria. Lesions will be compared to baseline measurements to assess progression. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From date of randomisation until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to 6 months after the last patient is randomised. |
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| E.5.2 | Secondary end point(s) |
Safety, tolerability (side effects) and feasibility of use (number of participants requiring dose delays or reductions and/or treatment withdrawal).
Objective response rate and clinical benefit rate as assessed by RECIST v1.1.
Overall survival (OS), time from enrolment to death with those still alive censored at date last seen.
Exploratory analysis: The influence of RET signalling pathway components expression on vandetanib activity.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 12 months after the last patient is randomised, except for: samples collected for future translational research (exploratory biomarkers)at baseline.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 25 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The study end date is deemed to be the date of last data capture. This will be the last patient’s study visit, or when 98 disease progression events have been reported, whichever is later. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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