Condition category
Cancer
Date applied
11/11/2015
Date assigned
11/11/2015
Last edited
22/01/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Public

Primary contact

Dr Joanna Smith

ORCID ID

Contact details

6th Floor
Neuadd Meirionnydd
Heath Park
Cardiff
CF14 4YS
United Kingdom

Additional identifiers

EudraCT number

2014-001208-23

ClinicalTrials.gov number

NCT02530411

Protocol/serial number

18232

Study information

Scientific title

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

Acronym

Study hypothesis

The aim of this study is to establish whether the combination of vandetanib and fulvestrant will improve clinical outcome in patients with endocrine resistant advanced breast cancer.

Ethics approval

Wales Research Ethics Committee 3, 18/12/2014, ref: 14/WA/1219

Study design

Randomised double-blind placebo controlled phase II study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Topic: Cancer; Subtopic: Breast Cancer; Disease: Breast

Intervention

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: Participants will receive Fulvestrant at 500mg IM on Day 1 and Day 15 of Cycle 1 then on Day 1 only of each subsequent cycle, and Vandetanib 300 mg po daily from Day 1 of Cycle 1 onwards.

Control arm: Participants receive Fulvestrant at 500mg IM on Day 1 and Day 15 of Cycle 1 then on Day 1 only of each subsequent cycle, and Placebo po daily from Day 1 Cycle 1 onwards.

Patients in both trial arms will be assessed on weeks 4, 8, 12, 16, 20, 24 of treatment and then every 12 weeks up to and including week 60. Treatment and assessment will continue until disease progression, unacceptable toxicity, withdrawal of consent or death. Patients that have not progressed by week 60 can remain on trial therapy indefinitely at the discretion of the local Principal Investigator.

Intervention type

Drug

Phase

Phase II

Drug names

Vandetanib

Primary outcome measures

Progression-free survival is assessed using RECIST V1.1 criteria over an estimated period of up to 45 months.

Secondary outcome measures

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

Overall trial start date

01/10/2014

Overall trial end date

31/12/2018

Reason abandoned

Eligibility

Participant 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 <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:
9.1. Absolute Neutrophil Count (ANC) = 1.0 x 109/L
9.2. Platelets (plts) = 100 x 109/L
9.3. Haemoglobin (Hgb) = 9 g/dl (Note: any blood transfusion 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

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

Planned Sample Size: 160; UK Sample Size: 160

Participant 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 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

Recruitment start date

20/04/2015

Recruitment end date

28/02/2017

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Velindre Cancer Centre
Velindre Road
Cardiff
CF14 2TL
United Kingdom

Trial participating centre

Royal United Hospital
Combe Park
Bath
BA1 3NG
United Kingdom

Trial participating centre

Royal Cornwall Hospital
2 Penventinnie Lane Treliske
Truro
TR1 3LQ
United Kingdom

Trial participating centre

Royal Bournemouth Hospital
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Trial participating centre

Weston General Hospital
Grange Road
Weston-super-Mare
BS23 4TQ
United Kingdom

Trial participating centre

Peterborough Hospital
Edith Cavell Campus Peterborough City Hospital Bretton Gate
Peterborough
PE3 9GZ
United Kingdom

Trial participating centre

Hinchingbrooke Hospital
Hinchingbrooke Park Hinchingbrooke
Huntingdon
PE29 6NT
United Kingdom

Trial participating centre

Colchester General Hospital
Turner Road
Colchester
CO4 5JL
United Kingdom

Trial participating centre

Kidderminster Hospital
Bewdley Road
Kidderminster
DY11 6R
United Kingdom

Trial participating centre

Worcestershire Royal Hospital
Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Trial participating centre

Alexandra Hospital
Woodrow Drive
Redditch
B98 7UB
United Kingdom

Trial participating centre

Queens Hospital
Belvedere Road
Burton-on-Trent
DE13 0RB
United Kingdom

Trial participating centre

Western General Hospital
Crewe Road South
Edinburgh
EH4 2XU

Trial participating centre

Gloucester Royal Hospital
Great Western Road
Gloucester
GL1 3NN

Trial participating centre

Cheltenham General Hospital
Sandford Road
Cheltenham
GL53 7AN
United Kingdom

Trial participating centre

City Hospital Birmingham
Dudley Road
Birmingham
B18 7QH
United Kingdom

Trial participating centre

Musgrove Park Hospital
Parkfield Drive
Taunton
TA1 5DA
United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

Poole Hospital
Longfleet Road
Poole
BH15 2JB
United Kingdom

Trial participating centre

Bristol Haematology and Oncology Centre
Horfield Road
Bristol
BS2 8ED
United Kingdom

Trial participating centre

Wales Cancer Trials Unit
6th Floor, Neuadd Meirionnydd University Hospital of Wales Heath Park
Cardiff
CF14 4YS
United Kingdom

Sponsor information

Organisation

Velindre NHS Trust

Sponsor details

Velindre Hospital
Velindre Road
Cardiff
CF14 2TL
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Industry

Funder name

AstraZeneca

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Data from all sites will be analysed when all participants have completed a minimum 12 months follow-up and at least 98 disease progression events are observed and published as soon as possible afterwards. The data will be disseminated via peer reviewed scientific journals, internal report, conference presentation, publication on website, and submission to regulatory authorities.

Intention to publish date

30/06/2019

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

22/01/2016: All participating trial sites have now been added, as well as the publication and dissemination plan and availability of participant level data. Further detail regarding dosing has also been added to the interventions section.