Conditions: Breast Cancer
Keywords: recurrent breast cancer stage IV breast cancer stage IIIB breast cancer stage IIIC breast cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 698
Healthy volunteers: no

Brief summary:
RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant, anastrozole, or exemestane may fight breast cancer by blocking the use of estrogen by the tumor cells or by lowering the amount of estrogen the body makes. It is not yet known whether giving fulvestrant together with anastrozole is more effective than giving fulvestrant together with a placebo or exemestane alone in treating breast cancer.

PURPOSE: This randomized phase III trial is studying fulvestrant and anastrozole to see how well they work compared to fulvestrant and a placebo or exemestane alone in treating postmenopausal women with locally advanced or metastatic breast cancer.

Detailed description:
OBJECTIVES:

Primary

* Compare progression-free survival of postmenopausal women with estrogen receptor- and/or progesterone receptor-positive, locally advanced or metastatic breast cancer that relapsed or progressed during prior treatment with nonsteroidal aromatase inhibitors treated with fulvestrant with vs without anastrozole vs exemestane alone.

Secondary

* Compare the objective complete response (CR) and partial response (PR) rate and duration of response in patients treated with these regimens.
* Compare the clinical benefit (i.e., 6-month CR, PR, and stable disease) rate and duration of clinical benefit in patients treated with these regimens.
* Compare time to treatment failure in patients treated with these regimens.
* Compare the overall survival of patients treated with these regimens.
* Compare the tolerability of these regimens in these patients.

OUTLINE: This is a randomized, partially double-blind and placebo-controlled, multicenter study. Patients are stratified according to the setting in which prior nonsteroidal aromatase-inhibitor therapy was given (adjuvant therapy vs first-line therapy) and participating center. Patients are randomized to 1 of 3 treatment arms.

* Arm I (fulvestrant and anastrozole): Patients receive fulvestrant intramuscularly (IM) on days 1, 15, and 29 and then once monthly. Patients receive oral anastrozole once daily.
* Arm II (fulvestrant and placebo): Patients receive fulvestrant as in arm I and oral placebo once daily.
* Arm III (exemestane alone): Patients receive oral exemestane once daily. In all arms, treatment repeats every month in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for survival.

PROJECTED ACCRUAL: A total of 750 patients (250 per treatment arm) will be accrued for this study.

Arms:
arm 1: Arimidex/placebo comparator is blinded Faslodex (fulvestrant) IM on day 1,15,29 and monthly thereafter Placebo orally once a day arm 2: Arimidex/placebo comparator is blinded Faslodex (fulvestrant) IM on day 1,15,29 and monthly thereafter Arimidex (anastrozole) orally once a day arm 3: exemestane orally once a day

Interventions: intervention 1: Anastrozole intervention 2: Exemestane intervention 3: Fulvestrant
Intervention descriptions: intervention 1: This may be Anastrazole OR a placebo intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
SoFEA Protocol 
Protocol date:  Final draft version 1 dated 20 June 2003 
Amended: Version 2 dated 28 October 2003 
Amended: Version 3 dated 16 December 2003 
Amended: Version 4 dated 26 January 2004 
Amended: Version 5 dated 02 August 2004 
Amended: Version 6 dated 17
t h November 2006 
Amended: Version 7 dated 6
t h December 2007 
Amended: Version 8 dated 21st January 2008 
Amended: version 9 dated 19 June 2008 
 
 
 
  
 
 
 
 
 
 
 
 
 
Study  of  Faslodex  
with or without concomitant Arimidex vs Exemestane  
following progression on non-steroidal Aromatase inhibitors 
 
 
 
A partially-blind phase III randomised trial of Fulvestrant (FaslodexTM) 
with or without concomitant Anastrozole (ArimidexTM) 
 compared with exemestane in postmenopausal women with ER+ve 
locally advanced/metastatic breast cancer 
following progression on non-steroidal aromatase inhibitors 
 
PROTOCOL 
 
EudraCT No: 2004-000093-30  
                    ISRCTN No:     44195747 
Protocol Number: ICR-CTSU/2006/10006 
 
 
 
 
 
This protocol is a controlled document and should not be copied, distributed or 
reproduced without the written permission of the ICR-CTSU. 
 


SoFEA Protocol 
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 PROTOCOL Version 9  – 19 June 2008 
 
 
 TRIAL MANAGEMENT GROUP: 
Dr Stephen RD Johnston (Chief Investigator) 
Professor Mitch Dowsett, Professor David Cameron, Dr David Dodwell, Professor Tony Howell, 
Professor Judith Bliss, Mrs Gill Coombes, Dr Andrew Wardley, 
SoFEA Trial Coordinators 
 
TRIALS UNIT CONTACTS: 
 
 
 
 
 
ICR Clinical Trials & Statistics Unit (ICR-CTSU) 
ISD Cancer Clinical Trials Team** 
Section of Clinical Trials 
The Institute of Cancer Research 
1st Floor Gyle Square, Area 159c 
 
Sir Richard Doll Building 
South Gyle 
Cotswold Road 
Edinburgh  
Sutton, Surrey, SM2 5NG, UK 
EH12 9EB  
Tel: +44 (0) 20 8722 4039 / 4062 
Tel: +44 (0) 131 275  6746 
Fax: +44 (0) 20 8770 7876 
Fax: +44 (0) 131 275 7512 
email: sofea-icrctsu@icr.ac.uk 
email: sofea@isd.csa.scot.nhs.uk 
 
 
**Information and Statistics Division 
 
Scientific Correspondence to: Dr Stephen RD Johnston, MA, PhD, FRCP, 
Department of Medicine (Breast Unit), 
The Royal Marsden NHS Foundation Trust & Institute of Cancer Research, 
Fulham Road, London SW3 6JJ, UK. 
Tel:  +44 (0) 20 7808 2745 
Fax: +44 (0) 20 7808 2563 
E-mail: Stephen.Johnston@rmh.nhs.uk 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
The SoFEA trial has been scientifically approved 
by the Clinical Trials Awards and Advisory Committee (CTAAC) 
 of Cancer Research UK and the Medical Research Council (February 2003) 
and is thus part of the NCRN/NCRI portfolio of breast cancer trials.  
The trial meets the criteria for R&D support as outlined  
in the Statement of Partnership on Non-Commercial R&D in the NHS in England. 
SoFEA TRIAL  - FINAL PROTOCOL  
Approved by:            
 
                             
 
 
Dr Stephen Johnston 
Date: 19 June 2008  


SoFEA Protocol 
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TABLE OF CONTENTS 
TRIAL SCHEMA..................................................................................................................1 
TRIAL SUMMARY...............................................................................................................2 
1.  
Background .............................................................................................................4 
1.1 
Clinical Setting ...................................................................................................................... 4 
1.2 
Acquired Resistance to Aromatase Inhibitors ....................................................................... 4 
1.3 
Pre-clinical Pharmacology of Faslodex ................................................................................. 5 
1.4 
Clinical Development of Faslodex......................................................................................... 5 
1.5 
Scientific Rationale for Study ................................................................................................ 6 
2.  
Aims of study ..........................................................................................................7 
2.1 
The primary aims of the study............................................................................................... 7 
2.2 
The secondary aims of the study .......................................................................................... 7 
2.3  
The exploratory aims of the study ......................................................................................... 7 
3.  
Study Design ...........................................................................................................8 
3.1 
Study treatments ................................................................................................................... 8 
3.2 
When to stop previous NSAI treatment............................................................................. 8 
4.  
Patient Selection and Eligibility.............................................................................9 
4.1 
Source of patients ................................................................................................................. 9 
4.2  
Number of patients................................................................................................................ 9 
4.3 
Inclusion Criteria ................................................................................................................... 9 
4.4 
Exclusion Criteria ................................................................................................................ 10 
5.  
Randomisation ......................................................................................................11 
5.1  
Randomisation Procedures................................................................................................. 11 
5.2  
Stratification ........................................................................................................................ 11 
5.3  
Following randomisation ..................................................................................................... 11 
6.  
Trial Evaluations ...................................................................................................12 
6.1 
At Baseline.......................................................................................................................... 12 
6.2 
During Study ....................................................................................................................... 12 
6.3 
Patient follow up following progression or withdrawal from treatment. ............................... 12 
6.4 
Schema of Trial Evaluations ............................................................................................ 13 
7.  
Trial Treatment ......................................................................................................14 
7.1 
Drug Administration: Route and Dose Schedule................................................................. 14 
7.2 
Formulation, Presentation and Storage .............................................................................. 15 
7.3 
Drug labelling ...................................................................................................................... 16 
7.4 
Prescriptions ....................................................................................................................... 16 
7.5 
Code Breaking .................................................................................................................... 16 
7.6 
Drug Accountability ............................................................................................................. 17 
8.  
Pharmacovigilance ...............................................................................................18 
8.1  
Adverse Event (AE)............................................................................................................. 18 
8.2 
Serious Adverse Events (SAE) ........................................................................................... 19 
8.3 
Recording and Reporting of Serious Adverse Events......................................................... 19 
8.4  
Follow up of Serious Adverse Event ................................................................................... 20 
8.5 
Review of Serious Adverse Event....................................................................................... 20 
8.6 
Reporting of SUSARs to MHRA and the Main REC............................................................ 20 
8.7 
Annual Reporting of Serious Adverse Events ..................................................................... 20 
8.8 
Flow diagram of SAEs reporting, and action following the report. ...................................... 21 
 


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9 
Statistical Considerations........................................................................................22 
9.1  
Stratification ........................................................................................................................ 22 
9.2  
Sample size......................................................................................................................... 22 
9.3  
Analysis methods ................................................................................................................ 23 
9.4 
Data monitoring and interim analyses................................................................................. 23 
9.5  
End of Study........................................................................................................................ 24 
9.6  
Analyses for Publication...................................................................................................... 24 
9.7 
Publishing policy ................................................................................................................. 24 
10.  
Research Governance ..........................................................................................25 
10.1 
Trial Administration ............................................................................................................. 25 
10.2 
Data Management............................................................................................................... 26 
10.3 
Protocol Compliance........................................................................................................... 26 
10.4 
Data Acquisition and On-site Monitoring / Auditing............................................................. 26 
10.5 
Financial Matters................................................................................................................. 27 
11.  
Clinical Risk Assessment.....................................................................................27 
12.  
Confidentiality and Liability .................................................................................28 
12.1 
Liability / Indemnity / Insurance........................................................................................... 28 
12.2 
Patient Confidentiality ......................................................................................................... 28 
12.3 
Ethics Issues....................................................................................................................... 28 
13.  
References.............................................................................................................29 
APPENDIX A -Translational Correlative Science Studies associated with SoFEA ....31 
APPENDIX B - Response Evaluation Criteria in Solid Tumours (RECIST) .................34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TRIAL SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ER+ve postmenopausal patients 
with locally advanced/metastatic  breast cancer 
who have progressed following treatment 
with non-steroidal aromatase inhibitors 
   Faslodex + Arimidex 
250 patients 
 
 
Each participating centre will be affiliated to one Trials Unit: 
ICR-Clinical Trials and Statistics Unit (ICR-CTSU), Sutton, Surrey 
OR ISD Cancer Clinical Trials Team, Edinburgh 
 
RANDOMISATION 
 
 
 Consent eligible patients for randomisation 
Patients continue treatment until disease progression 
Follow up for life 
   Faslodex + Placebo 
250 patients 
exemestane 
250 patients 


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TRIAL SUMMARY 
 
TITLE: 
A Partially-Blind Phase III Randomised Trial of Fulvestrant (FaslodexTM) 
with or without concomitant Anastrozole (ArimidexTM) compared with 
exemestane in postmenopausal women with ER+ve locally advanced / 
metastatic breast cancer following progression on non-steroidal aromatase 
inhibitors (NSAIs).  
 
OBJECTIVES: 
Primary: 
1.  To compare the progression-free survival of patients treated with 
Faslodex plus concomitant Arimidex (F+A) versus Faslodex (F) alone. 
2.  To compare the progression-free survival of patients treated with 
Faslodex (F) alone versus those treated with the current standard, 
exemestane (E). 
 
Secondary:  
1. 
To assess the objective tumour response rate (CR [Complete 
Response] + PR [Partial Response]), duration of response, clinical 
benefit rate (CR/PR + Stable Disease (SD) ≥6 months), duration of 
clinical benefit, time to treatment failure, and overall survival of patients 
treated with Faslodex plus concomitant Arimidex (F+A) compared with 
Faslodex (F) alone. 
2. 
To assess the objective response rate, duration of response, clinical 
benefit rate, duration of clinical benefit, time to treatment failure, 
progression-free and overall survival of patients treated with Faslodex 
(without concomitant Arimidex) compared with exemestane.  
3. 
In the case that concomitant use of Arimidex with Faslodex provides 
equivalent outcome to Faslodex alone, to compare the progression-
free survival of all Faslodex treated patients with those treated with 
exemestane. 
4. 
To determine the tolerability of Faslodex with or without concomitant 
Arimidex, and compared with exemestane. 
 
Exploratory: 
To establish in accessible tumour biopsies from as many patients as 
possible relapsing on NSAIs: tumour oestrogen receptor (ER) expression 
and activation status (i.e. phosphorylation status); tumour epidermal growth 
factor (EGFR) / transmembrane human epidermal growth factor receptor 
(HER2) expression and activation of the intracellular signalling pathways. 
 
TRIAL DESIGN: 
A partially-blind, randomised, multicentre phase III trial of Faslodex plus 
concomitant Arimidex versus Faslodex plus Arimidex-Placebo versus 
exemestane in postmenopausal locally advanced / metastatic breast 
cancer patients who have progressed on NSAIs. 
 
Randomisation to Faslodex ± Arimidex / Arimidex-Placebo or exemestane 
will be open (1:1:1). For Faslodex treated patients the randomisation to 
Arimidex or Arimidex-Placebo will be double-blind. 


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TYPE AND NUMBER:  
Patients will be postmenopausal women with measurable / evaluable 
oestrogen receptor positive (ER+ve) and / or progesterone receptor positive 
(PgR+ve) locally advanced / metastatic breast cancer who have progressed 
during treatment with an NSAI either as adjuvant therapy or as first-line 
treatment for locally advanced / metastatic disease, and who are suitable 
for further endocrine therapy. 
 
 
A total of 750 patients will be recruited. There will be 250 patients treated 
with Faslodex plus Arimidex, 250 patients treated with Faslodex + 
Arimidex-Placebo, and 250 patients treated with exemestane. 
 
 
TRIAL TREATMENT: 
Patients randomised to Faslodex: 
A loading dose of 500 mg intramuscular (i.m.) Faslodex on Day 1, followed 
by 250 mg i.m. on days 15 and 29, and thereafter continued at 250 mg i.m. 
monthly. 
 
In addition, all Faslodex patients will be randomised (double-blind) to either 
Arimidex 1mg orally once daily or matching Arimidex-Placebo orally once 
daily. 
 
 
Patients randomised to exemestane: 
Patients will receive exemestane 25 mg orally once daily, continuously. 
 
DURATION OF 
Until evidence of disease progression, or withdrawal of treatment  
TREATMENT: 
due to any drug related serious adverse event or patient choice. 
 
 
 
PRIMARY  
Progression-free survival (PFS) 
ENDPOINTS: 
 
 
 
SECONDARY 
Objective Tumour Response Rate (CR + PR) 
ENDPOINTS: 
Duration of Objective Tumour Response 
 
Clinical Benefit Rate 
 
Duration of Clinical Benefit 
 
Time to Treatment Failure 
 
Overall Survival 
 
Tolerability of Faslodex (± Arimidex) and exemestane 
 
 
In the case that the primary endpoint analysis of Faslodex versus Faslodex 
plus Arimidex shows equivalence (section 9.2) then a secondary analysis 
comparing the PFS of all Faslodex treated patients with that of exemestane 
treated patients will be performed.  
 
EXPLORATORY  
ENDPOINTS: 
Correlative Biological Studies of ER, EGFR / HER2 and mitogenactivated 
protein kinases (MAPK) / externally reglulated kinases (ERK) / insulin-like 
growth factor receptor (IGFR) and (product of the normal gene 
homologue of v-akt) AKT signalling in tumour biopsies at randomisation. 
 


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1.  
Background 
 
1.1 
Clinical Setting 
 
Non-steroidal aromatase inhibitors (NSAIs) such as Anastrozole (ArimidexTM), or letrozole 
(FemaraTM) are standard endocrine therapy for postmenopausal women with oestrogen 
receptor positive (ER+ve) advanced breast cancer who relapse after previous tamoxifen 
therapy [1] [2]. Recent randomised trials have shown that NSAIs are superior to tamoxifen as 
first-line therapy in metastatic disease [3] [4], while in the adjuvant setting preliminary data 
from the ATAC trial in ER+ve postmenopausal primary breast cancer have shown improved 
disease free survival for Arimidex in comparison with tamoxifen [5]. As a consequence it is 
likely that an increasing number of ER+ve postmenopausal women may be treated with an 
aromatase inhibitor (AI) as their initial endocrine therapy of choice. 
 
Breast cancer cells can adapt to the low levels of oestrogen induced by long-term oestrogen 
deprivation (LTED) with AIs, such that eventually patients relapse with resistant disease. If 
these patients still exhibit clinical features suggestive of hormone sensitivity at the time of 
relapse (e.g. retained tumour ER expression, durable response as first-line therapy or long 
disease-free interval in the adjuvant setting, soft-tissue indolent disease at subsequent 
progression, etc.), several questions arise. Firstly, are such patients suitable for further 
endocrine therapy after failure of an NSAI? At a clinical level, third-line responses have been 
recorded with the steroidal AI exemestane, although the mechanism for any partial non-cross 
resistance with the non-steroidal aromatase inhibitor is currently unclear [6]. Secondly, what 
would the endocrine therapy of choice be following failure of AIs - is there evidence they might 
respond to an antioestrogen?  In addition to understanding mechanisms of acquired 
resistance, endocrine therapies which are effective following AIs are needed. 
 
1.2 
Acquired Resistance to Aromatase Inhibitors 
 
There are emerging data which suggest that endocrine sensitivity may not only be maintained 
but also enhanced following acquired resistance to long-term oestrogen deprivation (LTED) 
with AIs. In the laboratory, data suggest that hormone sensitive MCF-7 breast cancer cells 
treated by LTED eventually adapt and become hypersensitive to the very low levels of 
oestradiol (E2) [7-9]. In part this is caused by an adaptive increase in ER expression and 
function [10]. In addition there is evidence for “cross-talk” between various growth factor 
receptor signalling pathways and ER at the time of relapse, with ER becoming activated and 
super-sensitised by a number of different intracellular kinases, including mitogen-activated 
protein kinases (MAPKs) and the insulin-like growth factor (IGF) / AKT pathway [11-13].  
 
While ER may be expressed and hypersensitive in breast cancer cells which become resistant 
to LTED, there is evidence that they are cross-resistant with tamoxifen [14]. Indeed such cells 
may perceive tamoxifen as an agonist, being stimulated rather than growth inhibited. In 
contrast, ER dependent growth and gene transcription in these LTED resistant cells was 
dramatically inhibited by the non-agonist antioestrogen ICI 182780 (Faslodex) [10] [14]. The 
ability of Faslodex to downregulate ER levels and its associated lack of any agonist activity 
may be central to its mechanism of action in this scenario.  
 
As such it is envisaged that Faslodex could be an effective treatment option for ER+ve breast 
cancer following acquired resistance to LTED as a consequence of AI therapy. There are 
pharmacological reasons (relating to concentrations required to occupy ER) which suggest 
that Faslodex might be more effective in an environment of continued low oestrogen. Likewise, 
growth of breast cancer cells resistant to LTED and hypersensitive to oestrogen could become 
enhanced upon subsequent release from oestrogen deprivation (i.e. clinically equivalent to 
removal of the AI at the time of relapse / progression and restoration of physiological 
postmenopausal E2 levels). Although Faslodex can reduce the growth of resistant LTED cells 
in-vitro, it is clear that added oestrogen may reduce its growth inhibition. As such, the 
effectiveness of Faslodex following failure of AIs may be critically dependent on the 
background E2 levels. 


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1.3 
Pre-clinical Pharmacology of Faslodex 
 
Faslodex (fulvestrant or ICI 182780) is a pure steroidal antioestrogen devoid of agonist 
oestrogen-like activity both in breast and uterine tissues [15]. In-vitro Faslodex's binding 
affinity for the ER is approximately 100-fold greater than tamoxifen, and in ER+ve MCF-7 
breast cancer cells Faslodex, unlike tamoxifen, is a pure antagonist of oestrogen-regulated 
gene expression (Cathepsin D and pS2) [16]. ER expression is suppressed and 
downregulated by Faslodex, without any concomitant rise in epidermal growth factor receptor 
(EGFR) or transforming growth factor (TGF alpha) expression [17]. Other important anti-
proliferative effects of Faslodex on hormonally-regulated breast cancer cells include 
suppression of insulin-like growth factor receptor (IGF-1R) signalling [18] [19].  
 
In vitro studies have demonstrated that tamoxifen-resistant breast cancer cell lines remained 
sensitive to growth inhibition by Faslodex [20-22], while in vivo studies in athymic mice showed 
that Faslodex suppressed the growth of established MCF-7 xenografts for twice as long as 
tamoxifen and significantly delayed the onset of resistant tumour growth [23]. Taken 
collectively, these pre-clinical data suggest that Faslodex could be a more effective oestrogen 
antagonist than tamoxifen, and that the lack of adverse agonist effects on breast cancer cells 
may be advantageous in the endocrine-resistant setting. 
 
1.4 
Clinical Development of Faslodex 
 
1.4.1 Phase I / II Studies 
Initial clinical trials of Faslodex were undertaken with administration of a short acting, 
propylene glycol-based, formulation by daily intramuscular (i.m.) injections. In an open 
randomised study 56 postmenopausal patients with operable breast cancer were randomised 
to seven consecutive daily i.m. injections of either 6 mg or 18 mg Faslodex, or to no active 
treatment (observation control), for 1 week prior to surgery [24].  Faslodex resulted in a 
reduction in tumour cell proliferation as measured by Ki67 labelling index and a reduction or 
absence of expression of ER and progesterone receptors (PgR) in ER+ve tumours [24] [25]. In 
a much larger pre-operative study, 221 patients were randomised to receive either Faslodex 
over a range of doses (50, 125 or 250 mg i.m.) or tamoxifen (20 mg/day) or matching 
tamoxifen placebo for 14-21 days prior to surgery [26] [27]. A significant dose-dependent 
reduction in the levels of ER expression was observed across all three doses of Faslodex 
compared with placebo and with tamoxifen when given at the 250mg i.m. dose [26].   
 
The clinical efficacy of Faslodex in women with tamoxifen-refractory advanced breast cancer 
was shown in a small phase II trial in 19 patients who received the monthly i.m. formulation 
starting with 100mg in the first month, increasing to 250mg for the second and subsequent 
months [28]. Seven patients demonstrated a partial response in their tumour and six patients 
stable disease for at least 6 months. Overall the median duration of clinical benefit for the 13 
patients was 25 months. These data clearly confirmed the lack of cross-resistance with 
tamoxifen which had been suggested in pre-clinical studies, supporting a mechanism of action 
distinct from tamoxifen. Subsequently a comparison with a well-matched historical control 
group of patients treated with the progestin megestrol acetate suggested a longer duration of 
response for patients receiving Faslodex (26 months vs 14 months) [29]. 
 
1.4.2 Phase III studies 
Two phase III studies have compared the efficacy and tolerability of Faslodex (250mg 
administered once monthly) with Arimidex (1mg daily), in postmenopausal women whose 
disease had progressed on or after tamoxifen [30] [31]. The North American trial was a 
double-blind randomised trial and recruited 400 patients, whilst the second Rest of the World 
(ROW) trial was an open label randomised study. The median time to disease progression 
was numerically longer for Faslodex compared with Arimidex for both the North American (5.4 
vs. 3.4 months) and ROW (5.5 vs. 5.1 months) trials, but was not statistically significant. The 
objective response rates were not significantly different in either trial (17.5% for both arms in 
the North American trial, and 20.7 vs.15.7 % for Faslodex and Arimidex respectively in the 


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ROW trial). In those patients who responded, median duration of response to Faslodex and 
Arimidex was 19.3 months and 10.5 months, respectively, in the North American trial and 14.3 
months and 14.0 months, respectively, in the ROW trial. Overall, the incidence of adverse 
events was low, and in the double-blind double-dummy North American trial which included a 
placebo intra-muscular injection in the Arimidex treatment group, there was no difference in 
injection site reactions compared to the Faslodex treated patients [30]. This suggested that the 
drug itself does not induce any specific local reactions at the site of injection. 
  
1.5 
Scientific Rationale for Study 
 
The hypothesis to be tested in this study is that breast cancers which relapse after an NSAI 
such as Arimidex or letrozole (FemaraTM) contain enhanced and activated ER, and that an ER 
downregulator such as Faslodex is an effective treatment for such patients. Because these 
cancer cells may be hypersensitive to E2, it is hypothesised that Faslodex could be more 
effective in an environment of continued “low” compared with “normal physiological” 
postmenopausal E2 levels. Therefore the first primary aim of the study will be to compare, in a 
double-blind randomised trial, the progression-free survival of such patients following NSAI 
failure treated with Faslodex plus concomitant Arimidex (F+A) versus Faslodex alone (F + 
matching Arimidex-Placebo). A third arm will give a randomised reference control arm for the 
trial.  This will be exemestane, the current endocrine treatment of choice for those who 
progress following NSAI [6].  (The results of a recent UK survey concluded that 60% of 
oncologists would prescribe exemestane for patients who progress after response to Arimidex 
for 1st line metastatic breast cancer (unpublished)). The second primary aim of the study is, 
therefore, to compare Faslodex alone against the current standard treatment, exemestane. 
The two primary aims are therefore independent and distinct. This strategy allows any 
additional benefit by combining Faslodex with Arimidex to be set within the context of the 
relative efficacy of Faslodex and exemestane.   
 
An exploratory aim described in the associated translational correlative science studies will be 
to collect accessible tumour biopsies from as many patients as possible relapsing on NSAIs 
(Appendix A).Molecular, biochemical and cytological assessments will be made in tumour 
samples / cells of ER expression and activation status, together with studies of activated 
growth factor signalling pathways. The aim will be to substantiate that ER+ve breast cancers 
resistant to NSAIs contain upregulated / hypersensitive ER signalling, and that this together 
with the circulating E2 levels may determine the response to Faslodex. 
 
It is anticipated that this clinical study will establish a clear rationale for the sequential use of 
Faslodex in women with ER+ve breast cancer who relapse after NSAIs. It is likely that the 
majority of patients will have received Arimidex which is the most widely used NSAI in the UK, 
although some centres use letrozole (FemaraTM).  There are no randomised clinical trials of 
Faslodex in this setting - a small Phase II study has been started by the SAKK group in 
Switzerland, and in 17 patients they have reported 2 responses and 7 patients with stable 
disease for >24 weeks [32]. A Regulatory trial will be conducted outside the UK (by 
AstraZeneca) simply comparing Faslodex directly with exemestane. However this trial will not 
study the effect of Faslodex in the continuing presence of an aromatase inhibitor, providing a 
low-oestrogen environment. It is felt that the pre-clinical findings in resistant LTED cells of an 
activated and hypersensitive ER, together with resistance to tamoxifen yet retained sensitivity 
to Faslodex, strongly support a clinical trial being started now to define the clinical role of 
Faslodex in this setting, together with the optimal way of delivering the drug (i.e. with or 
without concomitant Arimidex). 


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2.  
Aims of study 
 
2.1 
The primary aims of the study 
 
• 
To compare the progression-free survival of patients treated with Faslodex plus 
concomitant Arimidex (F+A) versus Faslodex (F) alone. 
• 
To compare the progression-free survival of patients treated with Faslodex (F) 
alone versus those treated with the current standard, exemestane (E). 
 
2.2 
The secondary aims of the study 
 
• 
To assess the objective tumour response rate (CR + PR), duration of response, 
clinical benefit rate (CR/PR + SD ≥6 months), duration of clinical benefit, time to 
treatment failure, and overall survival of patients treated with Faslodex plus 
concomitant Arimidex (F+A) compared with Faslodex (F) alone. 
• 
To assess the objective response rate, duration of response, clinical benefit rate, 
duration of clinical benefit, time to treatment failure, progression-free and overall 
survival of patients treated with Faslodex (without concomitant Arimidex) compared 
with exemestane. 
• 
In the case that concomitant use of Arimidex with Faslodex provides equivalent 
outcome to Faslodex alone, to compare the progression-free survival of all 
Faslodex (F and F+A) treated patients with those treated with exemestane (E). 
• 
To determine the tolerability of Faslodex with or without concomitant Arimidex, and 
compared with exemestane. 
 
2.3  
The exploratory aims of the study 
 
• 
To establish in accessible tumour biopsies from as many patients as possible 
relapsing on NSAIs: tumour ER expression and activation status (i.e. 
phosphorylation status); tumour EGFR / HER2 expression and activation of the 
MAPK / ERK / IGFR / AKT signalling pathways. 


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3.  
Study Design 
 
3.1 
Study treatments 
 
 
This is a partially-blind, randomised, multicentre study for eligible patients with locally 
advanced / metastatic breast cancer who have progressed on the non-steroidal aromatase 
inhibitors (Arimidex or letrozole (FemaraTM)). The study will compare the progression-free 
survival of patients treated with Faslodex plus concomitant Arimidex (F+A) versus Faslodex 
(F) alone. All Faslodex treated patients will take either an Arimidex or an Arimidex-Placebo 
tablet once daily, and both patients and clinicians will be blinded to this treatment option (i.e. 
double-blind). A reference control arm will be included with the steroidal aromatase inhibitor 
exemestane (E) which is the current endocrine treatment of choice for such patients.  
 
Eligible patients will be randomised in a ratio of 1:1:1 to either: 
 
Faslodex  plus Arimidex-Placebo 
Faslodex will be administered in the first month using a loading dose schedule of 500mg i.m. 
on day 1, followed by 250 mg i.m. on days 15 and day 29, and 250 mg i.m. monthly thereafter 
(section 7.0). Patients will also receive Arimidex-Placebo 1mg orally once daily. 
 
Faslodex plus Arimidex 
Faslodex will be administered in the first month using a loading dose schedule of 500mg i.m. 
on day 1, followed by 250 mg i.m. on days 15 and day 29, and 250 mg i.m. monthly thereafter 
(section 7.0).  Patients will also receive Arimidex 1mg orally once daily. 
 
Exemestane 
Patients allocated to exemestane in the reference control arm will receive a 25mg tablet of 
exemestane once daily (section 7.0). 
 
For all patients, treatment should continue until evidence of disease progression, or withdrawal 
of treatment in the event of any drug related serious adverse events (SAEs)  or patient choice 
(patients are only considered as withdrawn from the trial if consent is relinquished). 
 
3.2 
When to stop previous NSAI treatment 
 
Breast cancer cells that are resistant to LTED and are hypersensitive to oestrogen could 
become enhanced upon subsequent release from oestrogen deprivation i.e. removal of NSAI 
(Arimidex or letrozole (FemaraTM)) at the time of relapse / progression and restoration of 
physiological postmenopausal E2 levels (oestradiol). 
 
The effectiveness of Faslodex following failure of NSAI may be critically dependant on the 
background E2 levels i.e Faslodex might be more effective in an environment of continued low 
oestrogen. 
 
An important part of the trial is to assess the effectiveness of Faslodex with or without 
Arimidex i.e. Faslodex alone versus Faslodex + Arimidex, therefore it is important not to stop 
previous NSAI, until the patient has been randomised and has started their allocated 
treatment. 
 
In patients who have consented to have blood samples taken for research, this effect will also 
be investigated by comparing E2 levels before and after 3 months of trial treatment. 
 


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4.  
Patient Selection and Eligibility 
 
4.1 
Source of patients 
 
Postmenopausal patients with ER and/or PgR +ve locally advanced / metastatic breast cancer 
will be recruited from clinics within UK (and possibly European) centres. Patients previously 
entered into trials of adjuvant therapy are eligible for inclusion in this trial. 
 
4.2  
Number of patients 
 
A total of 750 patients will be required.  
 
4.3 
Inclusion Criteria 
 
• 
Female postmenopausal patients defined as: 
i Age ≥ 60 years or 
ii Aged 45-59 with intact uterus and amenorrhoeic for at least 12 months or 
iii Any age having had a bilateral oophorectomy.  
• 
Histologically or cytologically confirmed adenocarcinoma of the breast. 
• 
Patients with original ER+ve and/or PgR+ve breast cancer which has relapsed or 
progressed during endocrine therapy with a single agent non-steroidal aromatase inhibitor 
(NSAI) given as either: 
• 
adjuvant treatment where the patient  received at least 12 months therapy, or 
• 
first-line therapy for locally advanced / metastatic disease. Patients treated with an 
NSAI as first-line therapy must have had either an objective response (CR/PR) or 
stabilisation of disease for at least 6 months. 
• 
Sites of metastatic disease which are measurable / evaluable (according to Response 
Evaluation Criteria in Solid Tumours (RECIST))  should be assessed and followed as 
either: 
• 
Measurable disease: must include at least one target marker lesion    OR: 
• 
Non-measurable disease (ie evaluable disease): must include at least one non-
target marker lesion 
• 
Patients with bone only metastases are eligible provided they have evaluable site of bone 
metastases that can be followed by Xray or MRI / CT scanning. 
• 
Patients already established on bisphosphonate therapy for at least 6 months may 
continue on bisphosphonates;  
• 
Patients who will be started on bisphosphonates for bone metastases must have 
concurrent soft tissue / visceral sites of disease as the measurable / evaluable target 
marker lesion(s)  
• 
WHO performance status 0, 1 or 2. 
• 
Prior therapy permissible: 
• 
Tamoxifen given in the adjuvant or neo-adjuvant setting only. 
• 
Prior chemotherapy in the adjuvant or neo-adjuvant setting.  
• 
Prior chemotherapy as first-line treatment for metastatic breast cancer followed by 
NSAI alone for at least 6 months.  
• 
Adequate haematological function defined by haemoglobin ≥10 g/dl, neutrophil count ≥1.5 
x 109/l and platelets ≥ 100 x 109/l. 
• 
Adequate hepatic function defined by AST and ALT ≤ 2.5 x upper limit of normal.  Alkaline 
phosphatase ≤ 5 x upper limit of normal, unless bone metastases in the absence of liver 
disease. Renal function adequate defined by creatinine <175 mmol/l. 
• 
Life expectancy of >3 months and suitable for further endocrine therapy. 
• 
Have given written informed consent and are available for prolonged follow-up. 


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4.4 
Exclusion Criteria 
 
• 
Patients whose primary breast cancer was classified as:  
i. 
ER -ve and PgR NK  
 
ii. 
ER -ve and PgR -ve   
iii. 
ER NK 
• 
Rapidly progressive visceral disease (i.e. lymphangitis carcinomatosa, diffuse hepatic 
involvement). 
• 
Patients with malignancies (other than breast cancer) within the last 5 years, except for 
adequately treated in situ carcinoma of the cervix or basal cell / squamous cell carcinoma 
of the skin. 
• 
Systemic corticosteroids for > 15 days within the last 4 weeks. 
• 
Investigational drugs given within the previous 4 weeks. 
• 
Patients known to be on any unlicensed non-cancer investigational agent. 
• 
Patients with thrombocytopaenia (platelets <100 x 109/l or on anti-coagulant therapy  
(contra-indicated due to risk of bleeding with i.m. injection of Faslodex). 
 


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5.  
Randomisation 
 
5.1  
Randomisation Procedures 
 
  
Patients are randomised by telephone through the affiliated Clinical Trials Unit:  
• 
ICR Clinical Trials and Statistics Unit (ICR-CTSU), Section of Clinical Trials, The 
Institute of Cancer Research (Sutton, Surrey) Tel:  020 8643 7150 (09.00 – 17.00 
Monday to Friday) 
• 
 ISD Cancer Clinical Trials Team (Edinburgh)   
 
Tel:  0131 275 7276   (09.00 – 17.00 Monday to Friday)  
 
Prior to randomisation an eligibility checklist must be completed by the clinician / research 
nurse.   
 
The following information will be required at randomisation: 
 
• 
Name of cancer centre (if applicable), name of hospital, consultant and person 
randomising patient. 
• 
Confirmation that patient is eligible for the trial by completion of the eligibility 
checklist.  
• 
Confirmation that patient has given written informed consent for randomisation. 
• 
Ascertainment whether the patient has given written informed consent for blood 
samples and / or tumour biopsies to be taken for research purposes. 
• 
Patient’s full name, hospital number, date of birth, NHS number. 
• 
Date and site of first relapse. 
• 
Date NSAI first prescribed and type i.e. Anastrozole (ArimidexTM) or Letrozole 
(FemaraTM). 
• 
Confirmation that the patient is continuing on NSAI. 
• 
Ascertainment whether NSAI has been given:  
i) 
as adjuvant treatment or 
ii) 
for locally advanced / metastatic disease. 
 
The caller will be given the patient’s unique trial identification number (Trial ID) and will be told 
whether the patient has been allocated to either: 
i) 
a Faslodex containing treatment or 
ii) 
exemestane.  
 
5.2  
Stratification 
At randomisation, patients will be stratified by: 
• 
centre 
• 
whether previous NSAI treatment was given for adjuvant or locally advanced / 
metastatic disease. 
 
Since the use of a particular NSAI (i.e. Arimidex or letrozole (FemaraTM)) is determined at a 
centre level, stratification by centre will additionally ensure balance for type of previous 
treatment. 
 
5.3  
Following randomisation 
 
• 
For patients allocated to one of the Faslodex containing treatments the relevant 
pharmacy department will be sent a fax confirming patient details and Trial ID 
together with instructions on dispensing the patient’s individual treatment.  (section 
7.4.1) 
 
For patients allocated to exemestane the clinician should then write a prescription as in routine clinical 
practice. 


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6.  
Trial Evaluations 
 
6.1 
At Baseline 
• 
Relevant past medical history and clinical examination. 
• 
Haematology and biochemistry. 
• 
Corecut or excision biopsy for assessment of ER, EGFR / HER2 & signalling pathways 
(Appendix A) in patients with accessible tumour who are willing to give consent to a 
biopsy.  
• 
9 ml blood sample for baseline endocrine evaluation (oestradiol or oestrone) whilst patient 
still taking NSAI - in patients willing to give consent. 
NB Declining provision of blood samples for research does not exclude a patient from 
entry into the trial. 
Tumour staging either by CT scan thorax and abdomen, chest X-ray, bone scan and / or 
skeletal survey, clinical photograph, etc. (Appendix B for definitions of evaluable sites of 
disease, and criteria for response assessment by RECIST). 
 
6.2 
During Study 
• 
Clinical assessment: monthly during the first 6 months, and every 3 months thereafter 
providing that disease is stable / responding and treatment continues. 
A nurse or qualified person delegated by the Principal Investigator may carry out the 
monthly treatment evaluation which may be completed as a telephone assessment (i.e. 
for patients randomised to exemestane). 
 
Telephone Assessments 
To avoid bias in toxicity reporting, monthly assessment (excluding 3 monthly assessment) 
may be carried out via telephone. However these must be consistent with clinic visits i.e. 
exactly the same toxicity questions should be asked in the same manner according to the 
CRF format. This will enable comparable assessments of all treatments. 
• 
Tumour evaluation every 3 months during treatment, and at time of discontinuation / 
withdrawal from treatment. Tumour assessment to be conducted by the same imaging 
technique used to evaluate the indicator lesions at baseline. 
(The investigator must complete the 3 monthly assessment of treatment evaluation 
and the patient must be present at these assessments). 
• 
Haematology and biochemistry every 3 months. 
• 
9 ml blood sample taken for endocrine evaluation (oestradiol or oestrone) at 3 months (or 
at disease progression if relapse is prior to 3 months). 
 
6.3 
Patient follow up following progression or withdrawal from treatment. 
Following progression / withdrawal patient will be seen as part of routine clinical practice and 
details of death will be recorded on CRFs.  
 
 
 


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6.4 
Schema of Trial Evaluations  
 
 
Time points 
 
 
   Investigations 
 
Screening – 
within 28 days 
prior to 
randomisation 
Before 
treatment 
begins 
Visit 1 
Day 1 (Should 
occur within 7 
days of 
randomisation) 
Day 15 
 
Month 1 
 
Day 29 
 
(Monthly 
assessment form) 
 
 
Month 2 
 
Day 57 
 
(3 - Monthly 
assessment form) 
 
 
Month 3 
 
Day 85 
 
(3 - Monthly 
assessment form) 
 
Month 4 
 
Day 113 
 
(Monthly  
assessment form) 
Month 5 
 
Day 141 
 
(Monthly  
assessment form) 
 
Month 6 
 
Day 169 
 
(3 - Monthly 
assessment form) 
 
Month 9 and 
every 3 
months 
thereafter 
 
(3 - Monthly 
assessment form) 
Withdrawal/ 
Disease 
Progression 
Histology and WHO 
performance status 
9 
(Eligibility Checklist) 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Details of Primary disease 
 
8 
9 
Initial Clinical 
Data  (Form 1a) 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Details of treatment for locally  
advanced/metastatic disease 
 
8 
9 
Relapse details 
(locally 
advanced or 
metastatic) 
(Form 1b) 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
Tumour assessment (Clinical 
examination / X-ray / 
Ultrasound / MRI / CT Scan / 
Other – same method to be 
used for each tumour site) 
8 
9 
Baseline 
Evaluation 
(Form 1c) 
8 
8 
8 
8 
9 
8 
8 
9 
9 
9 
(Tumour  
Evaluation at 
discontinuation / 
withdrawal from 
treatment form) 
 
 
Haematology / Biochemistry 
evaluation 
9 
(Eligibility Checklist) 
9 
(Form 1c) 
8 
8 
8 
8 
9 
8 
8 
9 
9 
8 
Toxicity reporting 
8 
8 
8 
8 
9 
9 
9 
9 
9 
9 
9 
9 
Treatment given 
 
Faslodex 
8 
8 
9 
(Initial Assessment 
of Faslodex 
Treatment form) 
9  
(Initial Assessment 
of Faslodex 
Treatment form) 
9 -  Patient to continue on Faslodex monthly 
8 
Arimidex/ placebo 
8 
8 
       9 - Patient to continue on Arimidex / Arimidex-Placebo - prescribed every 3 months  
8 
OR 
Exemestane 
8 
8 
       9 - Patient to continue on Exemestane - prescribed as per routine practice 
8 
Tissue samples  
(see Appendix A - only if 
patient has consented) 
For all blood samples complete ‘Blood sample form for Biological Studies’ (see Site Information File) and send samples to Royal Marsden Hospital by courier (DHL). 
Blood sample for endocrine 
evaluation 
(9mls) 
8 
9 
8 
8 
8 
8 
 
9 
 
8 
8 
8 
8 
9 
Only if relapse is 
prior to 3 months. 
Biopsy of accessible tumour  (see 
Appendix A) 
8 
9 
8 
8 
8 
8 
8 
8 
8 
8 
8 
8 
 
N.B. CRFs to be completed are given in parentheses.


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7.  
Trial Treatment 
Treatment must begin within 7 days following randomisation. 
 
7.1 
Drug Administration: Route and Dose Schedule 
 
7.1.1 Faslodex  
 Must be administered according to the manufacturers Summary of Product Characteristics 
(SmPC). 
 
Faslodex is to be administered by intramuscular (i.m.) injection into the gluteus maximus 
muscle by staff specifically trained to do so (section 7.3). Each injection must be administered 
slowly over at least 2 minutes. A small number of patients have reported minor discomfort 
following the injection. This may be relieved by gentle massage over the injection site. It is 
recommended that the patient lies on the opposite side from the injection site in bed on the 
night following the injection to prevent discomfort from pressure on the injection site. Some 
redness at the injection site has occasionally been reported which has resolved without 
treatment. No specific treatment is recommended but, if necessary, symptoms can be treated 
according to local hospital procedures. 
 
7.1.2 Faslodex Dose Schedule 
Faslodex will be administered in the first month using a loading dose schedule of 500 mg i.m. 
on day 1, delivered as 1 x 5 ml injection in left buttock and 1 x 5 ml injection in right buttock. 
This will be followed by a 250 mg i.m. injection (5 ml) on days 15 (+/- 3 days) and day 29 (+/- 3 
days), and 250 mg i.m. injection (5 ml) monthly thereafter (- 10 days to + 3 days) – until 
disease progression or withdrawal from treatment. 
 
Treatment Delays 
In the event that treatment cannot be given on the scheduled date, it is preferable to give 
treatments earlier rather than later, this is to ensure that blood levels are maintained.  The next 
cycle should also be timed from the actual date of injection, not the proposed date i.e. if the 
loading dose is given on 1st March (500 mg) and the next dose on the 15th March (250 mg) the 
next dose will be due on the 29th March but if this dose is brought forward to the 26th March 
(250 mg), the dosing continues monthly from the 26th and not the 29th. 
 
7.1.3 Arimidex / Arimidex-Placebo Tablets 
 Must be taken according to the manufacturer’s SmPC for Arimidex.   
 
Patients treated with Faslodex will also receive either 1 mg Arimidex or 1 mg Arimidex-
Placebo tablets orally once daily (assigned in a double-blind fashion [section 7.3.1]) – until 
disease progression or withdrawal from the study.   
 
7.1.4 Exemestane 
 Must be taken according to the manufacturer’s SmPC. 
 
Patients allocated to exemestane should be prescribed 25 mg exemestane to be taken orally 
once daily until disease progression or withdrawal from the study. Exemestane should be 
prescribed according to local practice; this is usually either dispensed from the hospital 
pharmacy or initially from the hospital pharmacy and thereafter prescribed via the patient’s GP.  
 


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7.2 
Formulation, Presentation and Storage 
 
7.2.1 Faslodex 
Faslodex will be supplied as a 5% oily solution in pre filled syringes for single dose use.  Each 
pre filled syringe will contain 250 mg of Faslodex (LA ICI 182780) in 5 mls, (i.e. at a 
concentration of 50 mg/ml), designated as Faslodex 5% w/v injection, formulation number 
F6521. The syringes must be stored between 2-8oC (not frozen) in a secure location in a 
pharmacy and protected from light.  
 
Temperature excursions should be minimised and comply with the manufacturer’s storage 
statement.  Departure from the recommended storage conditions has a cumulative effect on 
the product quality if the upper or lower limits are exceeded for a cumulative period of no more 
than 28 days over the duration of the claimed shelf life.   
 
 
 
Fridge breakdowns 
 In the event of a fridge breakdown the pharmacist should notify ICR-CTSU of the event for 
advice.  
 
7.2.2 Arimidex 
Arimidex will be supplied as pots of 112 tablets. Each tablet is white and film coated  
containing 1 mg Anastrozole and inactive substances Lactose, Povidone, Sodium Starch, 
Glycollate and Magnesium Stearate.  Arimidex should be stored below 30oC.  
 
7.2.3 Arimidex-Placebo 
 
Arimidex-Placebo will be supplied as pots of 112 tablets. Each tablet is white and film 
 
coated containing only the inactive substances Lactose, Povidone, Sodium Starch, 
 
Glycollate and Magnesium Stearate.  Storage conditions are as for Arimidex in order to 
 
maintain the Arimidex-Placebo blind. 
 
7.2.4 Exemestane 
For patients allocated exemestane, this will be prescribed by the investigator and dispensed 
as per routine practice (i.e. following the initial prescription from hospital pharmacy, clinicians 
may prefer patients to obtain further supplies via their GP). 
 
Each coated tablet contains 25 mg exemestane.  Exemestane should be stored below 25°C 
and protected from light. 
 


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7.3 
Drug labelling 
 
7.3.1  Arimidex / Arimidex-Placebo 
In addition to the supply of Faslodex, each hospital pharmacy department will be sent a supply 
of Arimidex / Arimidex-Placebo tablets in pots containing 112 tablets sufficient for a 3 month 
supply for each patient and allowing for some overage. Each pot of tablets will have been 
labelled with the name of the trial and ‘For Clinical Trials use only’ and will bear two tear off 
slips.  Each will specify that the contents are Arimidex / Arimidex-Placebo ‘Treatment A’ or 
Arimidex / Arimidex-Placebo ‘Treatment B’. 
 
Following randomisation, fax confirmation will be sent to pharmacy by the appropriate Trials 
Unit with patient details and allocated treatment as exemestane or Faslodex and ‘Treatment A’ 
or Faslodex and ‘Treatment B’.   
 
Following appropriate assignment of Arimidex / Arimidex-Placebo (‘Treatment A’ or ‘Treatment 
B’) the pharmacist must then complete details on the tear off labels as indicated.  The 1st tear 
off slip must be detached and filed as in routine practice within the pharmacy department. The 
2nd tear off slip should be attached to the patient’s prescription. 
 
The label on the pot as seen by the patient will contain information that conforms to standard 
detail requirements such as quantity, storage information, expiry date, batch number and any 
other pharmacy instructions. Each hospital pharmacist must also insert the name of the PI or 
hospital specific code by which the PI can be identified.  Contents will only be stated as ‘112 
Arimidex tablets 1mg or Placebo to match’.     
 
 
7.3.2  Faslodex 
Faslodex has been labelled to include standard detail requirements such as quantity, storage 
information, expiry date, batch number and any other pharmacy instructions. 
 
There are two labels to each 5 ml syringe box.  The pharmacist must complete both labels and 
then detach the tear off slip and file as in routine practice within the pharmacy department. 
 
7.3.3  Exemestane 
Should be labelled and dispensed according to standard local practice for medication 
dispensed within a clinical trial, but must include a ‘For clinical trial use only’ label. 
 
7.4 
Prescriptions 
 
The type of prescription used in this trial will be as is standard routine practice within each 
hospital.  There is no special prescription for SoFEA. 
 
7.5 
Code Breaking 
 
Unblinding is restricted to emergency situations and should only be used under circumstances 
where knowledge of the treatment is necessary for the proper clinical care of the patient.  If the 
treatment code is broken, the pharmacist must complete a patient code break form clearly 
stating the reason for the code break.  The form must then be signed, dated and returned to 
the appropriate Trials Unit. 
 
Each hospital pharmacy will be issued with one code break envelope which will specify 
treatment ‘A’ or ‘B’ as being Arimidex or Arimidex-Placebo.  This must only be broken by the 
pharmacist.  Details divulged to the clinician must only be in regard to specific treatment for 
the patient for whom the code is broken and no details should be given as to whether the 
specific patient was allocated to Treatment ‘A’ or Treatment ‘B’ i.e. clinicians must not find out 
which drug corresponds to treatment ‘A’ / ‘B’. 
 


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7.6 
Drug Accountability 
 
AstraZeneca are providing the supplies of Faslodex and Arimidex / Arimidex-Placebo free of 
charge to all participating centres via their drug handling company ‘DHP’.  ICR-CTSU will liaise 
closely with AstraZeneca and have prior agreement as to the specific contents of the bottles.   
 
As soon as each participating centre has Site Specific Approval (SSA), R&D approval and the 
contract agreement between the centre and the appropriate Trials Unit has been signed, ICR-
CTSU will fax DHP the details required to ensure that the initial supplies of both Faslodex (6 or 
12 pre-filled syringes, depending upon recruitment) and Arimidex / Arimidex-Placebo (6 or 12 
pots) are despatched without delay to the relevant hospital pharmacy department.  DHP will 
also notify ICR-CTSU that such deliveries have been despatched.   
 
Records must be kept for all deliveries and a copy of the order / delivery note placed in the 
Trial Information pack and kept within the pharmacy department as in routine practice.  At the 
end of the trial, it must be possible to reconcile supply and usage of stock.  Account must be 
given of any discrepancies and certificates of delivery and return must be signed.     
 
Each of the pharmacy departments must designate a responsible person for ensuring that:  
   
  investigational products are handled and stored safely and properly;  
  investigational products are dispensed only to trial patients and in accordance with              
 the protocol; 
  that there is a sufficient supply of investigational products for patients’ continued 
 treatment, and in a timely manner, contact ICR-CTSU for re-supply of stock;  
  investigational products expiry dates are monitored and are used in order of expiry 
 date order i.e. earliest expiry first; 
  and that any unused products are returned or destroyed locally. 
    
 


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8.  
Pharmacovigilance 
 
For the purpose of this trial, any detrimental change in the patient’s condition that occurs after 
randomisation and within 30 days of the last administration of randomised treatment,  which is 
not due to progression of disease (breast cancer), should be considered either as an AE or 
SAE.   
 
8.1  
Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a patient administered a drug; the event does 
not necessarily have a causal relationship with the treatment or usage. 
 
Whenever one or more signs and / or symptoms correspond to a disease or well-defined 
syndrome only the main disease / syndrome should be reported.  For each sign/symptom the 
highest grade observed since the last visit should be reported. 
 
8.1.1  Adverse Reaction 
Any untoward and unintended response in a patient to an investigational medicinal product 
which is related to any dose administered to that patient. 
 
For the purpose of the trial, AEs that are considered as ‘expected’ Adverse Reactions are 
listed below (these are a sub-set of reactions that are specified in individual drug SmPCs):- 
 
Drug 
Very common 
Common 
Uncommon 
Faslodex 
(Fulvestrant) 
 
Hot flushes 
 
Gastrointestinal disturbance 
including nausea, vomiting, 
diarrhoea and anorexia 
 
Rash 
 
Urinary tract infections 
 
Headache 
 
Asthenia 
 
Back pain 
 
Leucorrhoea 
 
Arimidex 
(Anastrozole) 
 
Hot flushes 
 
Asthenia 
 
Joint pain / Stiffness 
 
Vaginal dryness 
 
Hair thinning 
 
Rash 
 
Nausea 
 
Diarrhoea 
 
Headache 
 
Anorexia 
 
Hypercholesterolaemia 
 
Vomiting 
 
Somnolence 
Aromasin 
(exemestane) 
 
Hot flushes 
 
Nausea 
 
Fatigue 
 
Increased sweating and 
dizziness 
 
Headache 
 
Insomnia 
 
Pain 
 
Skin rash 
 
Abdominal pain 
 
Anorexia 
 
Vomiting 
 
Depression 
 
Alopecia 
 
Peripheral or leg oedema 
 
Constipation 
 
Dyspepsia 
 
 
The side effects of combining Faslodex and Arimidex are not known, but it is not expected that 
they will be any more severe than with either drug on its own. It is also not expected that there 
would be any greater risk of developing blood clots with either Faslodex, Arimidex or with the 
combination of the two medications than with any of the treatments that the patient has been 
prescribed previously. 


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8.2 
Serious Adverse Events (SAE) 
 
 
 ICH GCP defines an SAE as any untoward medical occurrence that:  
• 
Results in death. 
• 
Is life-threatening*. 
• 
Requires inpatient hospitalisation** or prolongation of existing hospitalisation** 
(excluding hospital admissions for study drug administration, or admission for palliative 
care, terminal care or elective surgery). 
• 
Results in persistent or significant disability / incapacity. 
• 
Is a congenital anomaly / birth defect  
• 
(Any untoward medical occurrence requiring medical intervention to prevent permanent 
impairment or damage). 
 
N.B. Details given above in parentheses are an expansion of the SAE definition by ICR-CTSU 
 
* 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at 
 
risk of death at the time of the event; it does not refer to an event that hypothetically might have 
 
caused death if it were more severe.  
 
** Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the 
 
hospitalisation is a precautionary measure, for continued observation. Hospitalisation for a pre- 
 
existing condition or for further disease progression, including elective procedures, which 
 
has not worsened, does not constitute a serious adverse event. 
 
In addition the following will also be included as an SAE within the SoFEA trial: 
 
• 
Incidence of second primaries regardless of whether they occur during or at anytime 
after treatment. 
 
Other important medical events that may not result in death, are not life threatening, or do 
not require hospitalisation may be considered a serious adverse event when, based upon 
appropriate medical judgement, the event may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above (excluding 
cancer or result of overdose). 
 
Signs and Symptoms of metastatic disease as determined by the Principal Investigator are 
not Serious Adverse Events. 
 
Hospitalisation or death due to disease progression should not be reported as an SAE. 
 
 
8.3 
Recording and Reporting of Serious Adverse Events 
 
 
Refer to flow diagram given in section 8.8 
 
 
An AE classified as an SAE under the definition given in section 8.2 must be reported within 
24 hours of the Principal Investigator or designated representative becoming aware of 
the event using the specific SAE form. The form must be sent by FAX to: 
 
ICR Clinical Trials and Statistics Unit (ICR-CTSU), Section of Clinical Trials,  
The Institute of Cancer Research SAE safety desk on 020 8722 4368.  
 
At the same time centres affiliated to the ISD Cancer Clinical Trials Team must also 
FAX a copy to ISD Cancer Clinical Trials Team on 0131 275 7512.  
 
These must be completed, signed and dated by the Principal Investigator or designated 
representative. 


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8.4  
Follow up of Serious Adverse Event 
 
The patient must be followed-up until clinical recovery is complete and laboratory results have 
returned to normal, or until disease has stabilised. Information on final diagnosis and outcome 
of SAE which may not be available at the time the SAE was initially reported should be 
completed on the relevant part of the original SAE form within 15 days of the initial report and 
faxed to ICR-CTSU (Centres affiliated to the ISD Cancer Clinical Trials Team must also FAX a 
copy to ISD Cancer Clinical Trials Team on 0131 275 7512). 
 
8.5 
Review of Serious Adverse Event 
 
Once the SAE has been received by ICR-CTSU it will be forwarded to the Chief Investigator 
(CI) or designated representative for review. 
 
Centres should respond immediately (within 6 days) to requests from the CI or designated 
representative (via ICR-CTSU) for further information that maybe required for final 
assessment. 
 
The CI or designated representative will assess the SAE in respect to the following definitions: 
 
Serious Adverse Reactions (SARs) are those SAEs, which are considered to be 
possibly/probably/definitely related to the trial treatment.   
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SARs, which are not 
classified as "expected".  
 
SUSARs require expedited reporting by trial sponsor (i.e. CI with ICR-CTSU) to MHRA and 
main REC, therefore every effort should be made to notify Trial Unit/s within the timeframe 
shown in section 8.3. 
 
8.6 
Reporting of SUSARs to MHRA and the Main REC 
 
If an SAE is defined as a SUSAR and is fatal or life threatening, ICR-CTSU will report this to 
the MHRA and Main REC within 7 days from the date of definition. 
 
If an SAE is defined as a SUSAR and is not fatal or life threatening, ICR-CTSU will report this 
to the MHRA and Main REC within 15 days.  
 
Additional relevant information may be requested from centres, to make the assessment, this 
should then be sent to ICR-CTSU within 6 days. 
 
8.7 
Annual Reporting of Serious Adverse Events 
 
An annual report will be provided to the MHRA and the Main REC after the end of the 
reporting year.  This will be defined as one year after the date when the Clinical Trials 
Authorisation (CTA) was obtained.  This report will be in the form specified by the MHRA and 
COREC. 


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8.8 
Flow diagram of SAEs reporting, and action following the report. 
 
Adverse event considered serious as defined 
by protocol section 8.2
Flow diagram for SAE reporting, and action following report
Adverse Event observed
 in trial participant
No immediate reporting
Serious adverse event requires immediate reporting.
COMPLETE TRIAL SPECIFIC SAE FORM
Fax to ICR-CTSU and ISD Cancer Clinical Trials Team
 (if applicable) within 24 hours of the investigator becoming aware 
of the event
Sites must respond immediately to 
requests for further information that 
may be required for CI assessment
Receipt of SAE acknowledged by 
ICR-CTSU personnel and any 
missing data requested
SAE forwarded to the Chief Investigator (CI) or nominated representative for assessment of relatedness and 
expectedness, and returned to the ICR-CTSU
Assessment of relatedness to study medication
CI (or nominated representative) assessment of 
expectedness of the SAR
SAE
No further reporting required
SAR
Reported to Main REC and 
MHRA annually.  Royal 
Marsden NHS Trust and 
ICR joint R&D will be 
notified annually.
SUSAR
Requiring expedited 
reporting
Yes
No
Both the PI and CI suspects SAE is unrelated)
PI and/or CI suspects SAE is related
Expected
Unexpected
SUSARs will be reported by 
ICR-CTSU to:
(i) Medicines & Healthcare products 
Regulatory Agency (MHRA) and Main 
Research Ethics Committee (Main 
REC) within 7 calendar days if fatal or life 
threatening or 15 calendar days if 
non fatal or non life threatening (of 
initial report, as per EU CTD)
(ii) Sponsor at the same time as (i)
(iii) Principal investigators at regular 
intervals
(iv) AstraZeneca at the same time as (i)
Outcome of SAE
Should be completed within 15 days 
of initial report.  Follow-up of the SAE 
should continue until recovery or 
condition is stable.
Principal Investigator assesses event for 
causality and seriousness


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9 
Statistical Considerations 
 
9.1  
Stratification 
 
At randomisation, patients will be stratified by: 
• 
centre 
• 
whether previous NSAI treatment was given for adjuvant or locally advanced / 
metastatic disease 
 
Since the use of a particular NSAI (i.e. Arimidex or letrozole [FemaraTM]) is determined at a 
centre level, stratification by centre will additionally ensure balance for type of previous 
treatment. 
 
Patients will be identified by a unique identifier (Trial ID) comprising centre number, patient 
number and appropriate stratification. Once a Trial ID has been assigned, no attempt should 
be made to use that number again if, for example, a patient withdraws, or if a Trial ID has been 
incorrectly allocated.  No patient should be randomised more than once into the trial.  
 
The randomisation process incorporates a computer generated programme for producing 
randomly balanced permuted blocks.  
 
9.2  
Sample size 
 
This trial will be undertaken in postmenopausal patients with advanced breast cancer who 
have failed an NSAI and has two primary aims. The sample size has been calculated to allow 
these two distinct analyses to be carried out independently.  
 
Faslodex plus Arimidex-Placebo (F) versus Faslodex plus concomitant Arimidex (F+A)  
 
The first primary aim of the trial is to detect an improvement in median progression-free 
survival (PFS) from 5.5 to 7.5 months in patients allocated to F+A compared with F. Patients 
entering this study will either be “first-line” having progressed on an NSAI in the adjuvant 
setting, or “second-line” having progressed in the advanced disease setting on first-line NSAI 
therapy. It is estimated that approximately 20% patients will be first-line, and 80% second-line. 
From previous published studies the median progression free survival for F was 166 days for 
second-line patients in trials 0020 and 0021 [30, 31]. It should be noted that patients in these 
previous Faslodex trials were tamoxifen-treated patients, but for the purpose of power 
calculations assumptions have been made that similar progression-free intervals will exist for 
patients who have failed NSAI therapy.  
 
In order to detect a hazard ratio of ≤0.73 for F +A compared to F, approximately 440 events 
are required to have occurred in the trial. Using an estimated accrual of just over 25 patients 
per month for 24 months, and a minimum follow-up of 6 months, approximately 250 patients 
will be required for each of the F+A and F groups. This would yield the 440 events required in 
order to detect a hazard ratio of ≤0.73 at a significance level of 5% (two sided) with 90% 
power.  
 
Faslodex (F) alone versus exemestane (E) 
 
The second primary aim of the trial compares the PFS of patients allocated to F with those 
allocated to the current standard therapy for these patients, E.  
 
In a Phase II study following failure of previous NSAI the median PFS with E (given mainly as 
3rd line therapy) was 90 days [6].  Due to the fact that these patients will have received NSAI 
as first-line therapy the anticipated median PFS for E treated patients may be higher than that 
seen in Lonning’s study [6]. If the median PFS is in fact 4 months, then 208 events per arm 


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would be required to compare it with the expected median PFS of 5.5 months in the F treated 
patients (translating to a hazard ratio of ≤0.73; α=0.05 (2 sided); 90% power). Approximately 
250 patients will therefore be allocated to E. 
 
Consequently, approximately 750 patients in total will be required for this trial, with the primary 
analysis occurring after 440 patients have progressed in the F+A and F groups. 
 
The AstraZeneca Regulatory study of Faslodex (EFECT) versus exemestane therapy in 
patients progressing on a first-line NSAI will recruit a total of 660 patients randomised 1:1 
between the arms. The results from this study will be compared with those from the current 
(SoFEA) protocol in a meta-analysis type overview undertaken after the completion of both 
studies. 
 
Conditional analysis of all Faslodex treated patients with exemestane 
 
If evidence is observed that the PFS of F and F+A is in fact approximately equivalent (two 
sided and as defined by the observed Δ and its associated precision) then an analysis of all 
patients allocated to receive F versus those allocated to E will be conducted. The chosen 
value of Δ will be defined in conjunction with the independent Data Monitoring and Ethics 
Committee (DMEC). This therefore represents a closed testing procedure and thus does not 
impact on the significance of the primary endpoint.   
 
9.3  
Analysis methods  
 
Objective tumour response rate and clinical benefit rate will be analysed using logistic 
regression. Duration of response and duration of clinical benefit, measured from the date of 
randomisation, will only be summarised. Time to progression and time to death will be 
analysed using the Logrank test and Cox proportional hazards models. Subgroup analyses will 
be performed according to response to prior NSAI therapy (i.e. for those who received NSAI 
for advanced disease and achieved a CR / PR), and also according to ER or EGFR / HER2 
expression and MAPK / ERK / IGF / AKT activation at the time of relapse in those where this 
has been analysed in excision biopsies.  The prognostic value of disease free interval prior to 
randomisation will be investigated. For tolerability, all adverse events, serious and non-
serious, will be recorded. In addition, data will be collected on weight gain, hot flushes, and 
injection site reactions.  
 
9.4 
Data monitoring and interim analyses 
 
An independent Data Monitoring and Ethics Committee (DMEC) will be established to oversee 
the safety and interim efficacy of the trial. This committee will be constituted according to MRC 
Good Clinical Practice (MRC GCP). The DMEC will meet on a regular basis as they see fit, but 
no less than annually. Following each meeting, the DMEC will report their findings and 
recommendations to the Trial Steering Committee (TSC) and to the Trial Management Group 
(TMG). Interim analysis (split by treatment group) of side-effects, tolerability, progression-free 
survival, objective tumour response rate (CR + PR), duration of response, clinical benefit rate 
(CR/PR + SD ≥6 months), duration of clinical benefit, time to treatment failure, and overall 
survival for all randomised patients will be supplied in strict confidence by the trial statisticians 
to the DMEC together with any other analyses that the DMEC may request. The complete 
DMEC reports will remain confidential to the DMEC members and statisticians providing the 
report, however the Chief Investigator and Trial Coordinators will receive subsets of the report 
as seen fit by the DMEC (e.g. accrual, compliance, data completeness). Basic accrual data 
and safety reports, aggregated across the two treatment groups will be produced at 
appropriate periodic intervals and distributed to the TMG and to AstraZeneca.  
 
The main criterion for early stopping of the trial by the TSC upon suggestion from the DMEC 
will be that evidence from the trial and from other sources suggests a) proof beyond 
reasonable doubt that for all, or for some types of patient, one treatment regimen is clearly 
indicated or contra-indicated in terms of a net difference in PFS and b) evidence that might 


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reasonably be expected to influence routine clinical practice.  Criteria for the above will usually 
be a difference in PFS significant at p<0.001 by overall log-rank analysis. No results on PFS 
will be made available to participants or AstraZeneca until the DMEC consider the results to be 
clinically and statistically informative. 
 
9.5  
End of Study 
 
For the purposes of Clinical Trial Authorisation (CTA) under the European Union Directive 
2001/20/EC, the study is deemed to have ended 30 days after the last patient remaining on 
treatment receives the last dose of the investigational medicinal product (IMP). 
 
Follow-up of all randomised patients will continue in the post-treatment phase. 
 
For the purposes of Main REC approval, the study end date is deemed to be the date of the 
last data capture.   
 
9.6  
Analyses for Publication 
 
 Unless the DMEC advises otherwise, it is expected that the first analyses for  
publication / 
presentation will be performed when the required number of events is  
reached.  All trial 
data are owned by the Trial Management Group (TMG).  
 
9.7 
Publishing policy 
 
All publications and presentations relating to the trial will be authorised by the TMG.  A writing 
committee may be appointed.  Authorship will include the principal investigators, statisticians and 
trial coordinators. Further authorship will be determined by centre accrual. The trials offices who 
have undertaken the data management and all participating centres will be acknowledged in the 
final manuscript according to patient accrual. 
 
Participants will only present data separately to the total data available, with the permission of 
the TMG, and not less than 6 months after publication of the main results. 
 
AstraZeneca has the right to review all abstracts, papers, or other research communications 
prior to their submission to journals, meetings, or conferences and all such communications 
will be circulated to the Trial Steering Committee (TSC) for their information and comment.  
AstraZeneca may request removal of propriety information and may suggest editorial changes 
in the papers to the TMG.  The TMG has final authority over the content of all publications.   
 
 


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10.  
Research Governance  
 
10.1 
Trial Administration  
 
Sponsorship activities and delegated responsibilities are shared between the employer of the 
Chief Investigator (The Royal Marsden NHS Foundation Trust) and The Institute of Cancer 
Research in accordance with The Medicines for Human Use (Clinical Trials) Regulations 2004 
and amendments and in line with the Research Governance Framework for Health and Social 
Care and the principles of GCP.  Both parties agree to allow inspection of sponsors' premises 
by the competent authorities.  
 
The Institute of Cancer Research is responsible for administering, funding and co-ordinating 
any required legal agreements and investigator statements. 
 
10.1.1 Chief Investigator responsibilities include:- 
• 
Trial authorisation (including responsibility for protocol, submissions to MHRA / COREC, 
informing ICR-CTSU of centres that have Site-Specific assessment (SSA), selection of 
investigators); 
• 
Ensuring that the trial is conducted in accordance with Good Clinical Practice – delegating 
responsibilities noted below to ICR-CTSU; 
• 
Pharmacovigiliance – The Chief Investigator or, in his absence, a designated 
representative is responsible for a prompt decision as to which serious adverse events are 
SUSARs, and for prompt reporting to ICR-CTSU.   Other responsibilities noted below are 
delegated to ICR-CTSU.   
 
10.1.2 ICR-CTSU responsibilities 
The Chief Investigator has delegated responsibility to ICR-CTSU for the trial conduct as 
specified in the agreement between the centre and ICR-CTSU / ISD Clinical Trials Team. 
 
ICR-CTSU has overall responsibility for facilitating and coordinating the conduct of the trial and 
is also responsible for collating data obtained, and undertaking and reporting interim and final 
analyses.   
 
10.1.2  Trials Units responsibilities:- 
The day to day management of the trial is being undertaken jointly by ICR-CTSU (Sutton) and 
ISD Cancer Clinical Trials Team (Edinburgh).  All data will be entered onto a database at ICR-
CTSU, and one at ISD Cancer Clinical Trials Team. 
 
The responsibilities of ICR-CTSU and / or ISD Cancer Clinical Trials Team for the day-to-day 
management of the trial will include the following: 
 
• 
Trial initiation visits to selected centres and early visits to the remainder; 
It is important that the investigator and their relevant personnel are available during 
these visits and that sufficient time is devoted to the process 
• 
communication with / submission to local ethics committees; 
• 
randomising patients; 
• 
submission of monthly accrual figures to the ICR-CTSU within the first week of each 
month; 
• 
receiving completed CRFs from the hospitals; 
• 
raising and resolving queries with local investigators; 
• 
logging data received; raising queries; 
• 
monitoring of centres at agreed frequency;  


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• 
informing ICR-CTSU (in writing) of Serious Adverse Events, code breaks, protocol 
violations; 
• 
requesting drug supply via ICR-CTSU; 
• 
circulating unexpected drug related SAEs and safety reports to centres. 
 
10.1.3 Site-Specific responsibilities:- 
 Local sites should conduct the trial in accordance with the clinical trials agreement, SOPs, 
principles of GCP and current trial protocol. 
 
10.2 
Data Management 
 
10.2.1  Case Report Forms (CRFs) 
Case Report Forms (CRFs), which are in the form of a booklet, should be completed for all 
patients and should not be made available to third parties.  
 
CRFs are in duplicate. The top copy must be sent by the designated staff member i.e. Data 
manager or Research nurse to the affiliated Trials Unit (either ICR-CTSU or ISD Cancer 
Clinical Trials Team) as soon as they are due. The bottom copy must be retained in the 
booklet and held by the investigator. All sections are to be completed on the form before 
sending or submitting to the affiliated Trials Unit. If information is not known it must be clearly 
stated.  
 
10.3 
Protocol Compliance 
 
SoFEA is being conducted in accordance with the professional and regulatory standards 
required for non-commercial research in the NHS under the EU Directive and principles of 
GCP. 
Staff from centres that have attended either the Investigator meeting and/or Nurses training 
day will not require start-up visits unless there is a specific request. 
 
 All staff who are to administer Faslodex will require training (section 7.3). 
 
10.4 
Data Acquisition and On-site Monitoring / Auditing 
 
By participating in the SoFEA trial the Principal Investigators at each centre are confirming 
agreement with his / her local NHS Trust to ensure that:  
 
• 
sufficient data is recorded for all participating patients to enable accurate linkage 
between hospital records and CRFs;  
• 
source data and all trial related documentation are accurate, complete, maintained 
and accessible for monitoring and audit visits; 
• 
all staff at their centre who are involved with the trial will meet the requirements of the 
EU Directive;  
• 
original consent forms are dated and signed by both  patient and investigator and are 
kept together in a central log together with a copy of the specific patient information 
sheet(s) given at the time of consent; 
• 
copies of CRF’s  are retained for 15 years to comply with international regulations; 
• 
staff will comply with the Trial Guidance Notes for SoFEA. 
 
 The affiliated Trials Unit will monitor receipt of CRFs and evaluate incoming CRFs for 
compliance with the protocol, inconsistencies and missing data. 
 
Participating centres may be monitored by the Trials Unit and possibly by Health Authorities. 
Monitoring by Trials Units will confirm compliance with the protocol and source data 
verification (SDV). 


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Site auditing/monitoring will be conducted at a proportion of participating centres at least once 
during the course of the trial.  If a monitoring visit is required the Trials Unit will contact the 
centre to discuss dates of proposed visit.  Once a date has been confirmed a list of names of 
patients whose notes will be monitored / audited during the visit will be sent to the centre.  This 
list will be sent out in advance to give sufficient time for the notes to be made available. (The 
Trial Statistician will decide what percentage of patients are to be monitored / audited). 
 
If any problems are detected in the course of the monitoring / auditing visits then the Principal 
Investigator and the Trials Unit will work together to resolve queries to determine the centre’s 
future participation in the study. 
 
10.5 
Financial Matters 
 
SoFEA is an investigator designed and led trial that has been subjected to independent peer 
review and approved by the Clinical Trials Awards and Advisory Committee (CTAAC) of 
Cancer Research (UK) and thus meets the criteria for R&D support as outlined in the 
Statement of Partnership on Non-Commercial R&D in the NHS in England.  
 
Research costs (to the Trials Units) are being funded via an educational grant provided by 
AstraZeneca.  Faslodex and Arimidex / Arimidex-Placebo are provided free of charge by Astra 
Zeneca.  If additional financial support is received from any other source, this will be made 
apparent to the Main REC and CTAAC, but will not require a protocol amendment. 
 
No individual per patient payment will be made to trusts or investigators, but NCRN (or 
regional equivalent) network resources should be made available as the trial is part of the 
NCRI trials portfolio by virtue of its approval by CTAAC. 
 
 
11.  
Clinical Risk Assessment 
 
Generic Risk Assessment Hazards to patients, study and organisation have been performed 
for the SoFEA Trial and have been considered low risk.   
 
 


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12.  
Confidentiality and Liability 
 
12.1 
Liability / Indemnity / Insurance 
 
This study is an investigator-led trial endorsed by the Clinical Trials Awards and Advisory 
Committee (CTAAC) of Cancer Research UK and the UK Medical Research Council. 
Indemnity for participating hospitals is provided by the usual NHS indemnity arrangements.  
 
12.2 
Patient Confidentiality 
 
The patient’s full name, date of birth, hospital number and NHS number (or Community Health 
Index and / or hospital number in Scotland) will be collected at randomisation to allow tracing 
through national records.  The personal data recorded on all documents will be regarded as 
confidential, and to preserve each subject's anonymity, only their initials and date of birth will 
be recorded on subsequent Case Report Forms.      
 
The investigator must keep a separate log of patients’ trial numbers, names, addresses and 
hospital numbers. The investigator must maintain in strict confidence trial documents, which 
are to be held in the local hospital (e.g. patients' written consent forms).  The investigator must 
ensure that patient’ confidentiality is maintained. 
 
ICR-CTSU / ISD Cancer Clinical Trials Team will maintain the confidentiality of all subject data 
and will not reproduce or disclose any information by which subjects could be identified, other 
than reporting of serious adverse events.  Representatives of the Trials Units will be required 
to have access to patient notes for quality assurance purposes but patients should be 
reassured that their confidentiality will be respected at all times.  (In the case of special 
problems and / or government queries, it is also necessary to have access to the complete 
study records, provided that patient confidentiality is protected). 
 
12.3 
Ethics Issues 
 
The trial will be performed in accordance with the recommendations guiding physicians in 
biomedical research involving human subjects adopted by the 18th World Medical Assembly, 
Helsinki, Finland, 1964 and later revisions. 
 
It is the responsibility of the investigator to obtain approval of the trial protocol and any 
subsequent amendment from the Main REC.  All correspondence relating to Research Ethics 
committees should be filed by the Investigator.  Copies of the Main REC approval should be 
forwarded to ICR-CTSU by the Chief Investigator. 
 
It is the responsibility of the investigator to give each patient, prior to inclusion in the trial, full and 
adequate verbal and written information regarding the objective and procedures of the trial and 
the possible risks involved. Patients must be informed about their right to withdraw from the trial 
and the possible risk involved. Written patient information must be given to each patient before 
enrolment. The written patient information is an approved patient information sheet according to 
national guidelines. It is the responsibility of the investigator to obtain signed informed consent 
from all patients prior to inclusion in the trial. 
 
The patient information sheet provided in the SoFEA trial should be provided in addition to the 
standard hormone therapy patient information sheet that is provided by the centre and used in 
routine practice.   
  
Patient identification data will be required at randomisation to assist with long-term follow-up.  


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McClelland RA, Manning DL, Gee JM, et al: Effects of short-term anti-estrogen treatment of 
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26. 
Robertson JF, Nicholson RI, Bundred N, J,, et al: Comparison of the short-term biological 
effects of 7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17b-diol 
(Faslodex) versus Tamoxifen in postmenopausal women with primary breast cancer. Cancer 
Res 61 (18): 6739-6746, 2001 
27. 
Robertson JF, Nicholson RI, Gee JMW, et al: The pharmacokinetics of single dose Faslodex 
(ICI 182780) in postmenopausal primary breast cancer - relationship with estrogen receptor 
downregulation. Proc Am Soc Clin Oncol 19: A362, 2000 
28. 
Howell A, DeFriend DJ, Robertson JF, et al: Response to a specific antioestrogen (ICI 
182780) in tamoxifen-resistant breast cancer. Lancet 345 (8941): 29-30, 1995 
29. 
Robertson JRF, Howell A, DeFriend DJ, et al: Duration of remission to ICI 182780 compared 
to megestrol acetate in tamoxifen resistant breast cancer. Breast 6 (4): 186-189, 1997 
30. 
Osborne CK, Pippen J, Jones SE, et al: Double-blind, randomised trial comparing the efficacy 
and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced 
breast cancer progressing on prior endocrine therapy: results of a North American Trial. J Clin 
Oncol 20 (16): 3386-3395, 2002 
31. 
Howell A, Robertson JRF, Albano J, et al: Fulvestrant, formerly ICI 182,780, is as effective as 
anastrozole in postmenopausal women with advanced breast cancer progressing after prior 
endocrine treatment. J Clin Oncol 20 (16):  3396-3403, 2002 
32. 
Perey L, Thurlimann B, Hawle H, et al: Fulvestrant (Faslodex) as hormonal treatment in 
postmenopausal patients with advanced breast cancer progressing after treatment with 
tamoxifen and aromatase inhibitors: an ongoing phase II SAAK trial. Eur J Cancer 38: S98 
223, 2002 
 
 
 


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APPENDIX A -Translational Correlative Science Studies associated with SoFEA 
 
AIM 
To conduct molecular, cytological and biochemical analyses in tissue and blood and to establish a 
scientific rationale for the use of the pure anti-oestrogen Faslodex in women with endocrine-sensitive 
breast cancer following failure of aromatase inhibition. 
 
Material for Study 
a) Acquisition of primary tumour specimen blocks for centralised assessment. 
b) Acquisition of metastatic tissue specimens at initiation of trial therapy. 
c) Creation of tissue microarrays. 
 
a) Acquisition of primary tumour specimen blocks for centralised assessment. 
 
Rationale 
 
Blocks of the primary tumour will be retrieved to assess baseline measurements of hormone and 
growth factor receptors and signal transduction components. These factors may predict for 
primary response to endocrine treatment, and it is hypothesised that acquired changes 
(particularly in growth factors) may account for the development of resistance [1, 2].  Therefore 
patterns of expression will be compared with metastatic tissue at relapse (see below) to gain 
insight into mechanisms of resistance to aromatase inhibitors (AIs).  
 
Practical aspects 
 
Details of the primary tumour will be collected on the initial clinical data form in the CRFs, which 
will include: 
 
• 
Date of original diagnosis 
• 
Name of reporting pathologist 
• 
Histology number 
• 
Location of paraffin blocks 
  
At the end of trial recruitment all paraffin-embedded blocks from the original primary tumour 
surgical specimen from as many patients as possible (who have given consent), will be requested 
by the Trials Unit to be sent by post to the Academic Department of Biochemistry, Royal Marsden 
NHS Foundation Trust, London SW3 6JJ.  In previous trials blocks have been acquired from up 
to 80% of trial patients. Up to 10 sections from a representative tumour block will be cut and 
stained by immuno-histochemistry (IHC) for hormone receptors (ER, PgR), peptide growth factor 
receptors (HER2, EGFR) and total/activated components of the MAPK and AKT signal 
transduction pathways. Antibodies for IHC use against phosphorylated (activated) kinases (ie P-
ERK1/2, P-p38MAPK, P-Akt) are in regular use in Professor Dowsett’s laboratory. Three x 600μm 
cores will be taken for the construction of tissue microarrays for the analysis of other molecular 
markers.  All blocks will be returned to the referring centre / pathology laboratory.  
 
b) Acquisition of metastatic tissue specimens at initiation of trial therapy.  
 
Rationale 
 
When available this tissue will be analysed with respect to the biomarkers and pathways 
discussed above.  Fresh frozen tissue will be used for gene expression profiling.  The tumour 
phenotype at relapse after aromatase inhibitor will be compared with the primary sample 
retrieved above, and will also be correlated with clinical response to treatment in the SoFEA trial.  
This may enable the identification of the molecular profiles / phenotypes at relapse on AIs which 
predict for sensitivity to Faslodex. 


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Practical aspects 
 
 
Wherever possible accessible metastatic deposits (such as skin nodules, locally advanced breast 
tumours or lymph nodes) will be sampled prior to trial initiation by core biopsy or surgical 
excision.  Specific written informed consent will be sought from patients for these biopsies.  From 
previous studies it is estimated that such tissue will be available in between 20-25% of patients 
eligible for the SoFEA trial.  Tissue will be split equally between fresh frozen (for mRNA and 
protein studies) and formalin fixation for IHC studies.  The fresh frozen tissue should be stored in 
liquid nitrogen and transferred to Academic Department of Biochemistry, Royal Marsden NHS 
Foundation Trust, London SW3 6JJ on cardice.  The formalin-fixed tissue should be sent to the 
same address at ambient temperature. 
 
The mRNA extracted from frozen tissue will be used for cDNA microarray gene expression 
studies.  Where indicated from the cDNA arrays or other parallel studies, real-time (quantitative) 
PCR of specific highlighted genes will be performed.  In addition protein extracts will be used to 
measure activated ER, activated ERK 1/2 and Akt, and IGFR / IRS signalling pathways by 
Western blotting.  At present antibodies against activated phosphorylated ER (ie at sites such as 
Ser118 and Ser167) are available for Western blot analysis only (in due course assays may be 
developed to study these by IHC in fixed tissues). 
 
Formalin-fixed metastatic pre-treatment tissue will be analysed by IHC for hormone receptors 
(ER, PgR), peptide growth factor receptors (HER2, EGFR) and total/activated components of 
various signal transduction pathways (i.e. P-ERK1/2, P-p38MAPK, P-Akt), and comparison made 
with primary breast cancer samples from the same patients.  This will allow an unique study of 
the intra-patient change in ER and growth factor signalling associated with acquired resistance to 
aromatase inhibitors, and will determine in-vivo whether cross-talk activation of ER accounts for 
resistance, and in particular whether this predicts for response to Faslodex in the context of the 
randomised trial. 
 
c)  Creation of tissue microarrays. 
 
Rationale 
Tumour specimens will also be used to create tissue microarrays as a resource for future studies.  
As antibodies against new biomarkers from various signal transduction pathways are discovered, 
these can be analysed retrospectively in the constructed tissue arrays from this treatment cohort.  
 
Practical aspects 
These tissue arrays will be created from available primary and metastatic blocks of tumour using 
protocols in routine use at the Academic Department of Biochemistry, Royal Marsden NHS 
Foundation Trust, London SW3 6JJ. .  Previous tissue microarrays from over 800 patients have 
been constructed as part of the national adjuvant TACT (Taxotere as Adjuvant Chemo Therapy) 
trial, as well as a pre- and post-tamoxifen resistance array from 56 patients with advanced breast 
cancer. 
 
 
 
 
 
 
 
 
 
 
 
References: 


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1. 
Ellis MJ, Coop A, Singh B, et al: (FemaraTM) is more effective neoadjuvant endocrine therapy 
than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast 
cancer: evidence from a phase III randomized trial. J Clin Oncol 19(18): 3808-16, 2001 
 
2. 
Dowsett M, Harper-Wynne C, Boeddinghaus I, et al: HER-2 amplification impedes the 
antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast 
cancer. Cancer Res 61(23): 8452-8, 2001 
 


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APPENDIX B - Response Evaluation Criteria in Solid Tumours (RECIST) 
 
 Quick Reference 
 
Eligibility 
 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumour response is the primary endpoint.  
Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed 
by imaging techniques and:-  
• 
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
• 
The same method of assessment and the same technique should be used to characterise 
each identified and reported lesion at baseline and during follow-up.  
• 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Methods of Measurement   
 
• 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be 
performed with cuts of 10 mm or less in slice thickness contiguously.  Spiral CT should be 
performed using a 5 mm contiguous reconstruction algorithm.  This applies to tumours of 
the chest, abdomen and pelvis.  Head and neck tumours and those of extremities usually 
require specific protocols. 
 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumour lesions.  It is, however, a possible alternative to 
clinical measurements of superficial palpable lymph nodes, subcutaneous lesions and 
thyroid nodules.  US might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 


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• 
The utilization of endoscopy and laparoscopy for objective tumour evaluation has not yet 
been fully and widely validated.  Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers.  
Therefore, the utilization of such techniques for objective tumour response should be 
restricted to validation purposes in specialized centers.  However, such techniques can be 
useful in confirming complete pathological response when biopsies are obtained. 
 
• 
Tumour markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response when all lesions have disappeared. 
 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases 
(e.g. after treatment to differentiate between residual benign lesions and residual 
malignant lesions in tumour types such as germ cell tumours). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
 
• 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumour. 
• 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence or absence of each should be noted throughout follow-up.  
 
Response Criteria 
Evaluation of target lesions 
 
* Complete Response   (CR): 
Disappearance of all target lesions. 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions.
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. 
 


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Evaluation of non-target lesions 
 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumour marker level. 
* Incomplete Response/          
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumour marker level above the normal limits. 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. (+)  
 
(+)  Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression 
status should be confirmed later on by the review panel (or study chair). 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria.  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response 
/ SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment.  
 
• 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 


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Confirmation 
• 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
• 
To be assigned a status of PR or CR, changes in tumour measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate.  
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study 
protocol.  
 
Duration of overall response 
• 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started. 
 
Duration of stable disease 
• 
SD is measured from the start of the treatment until the criteria for disease progression are met, 
taking as reference the smallest measurements recorded since the treatment started.  
• 
The clinical relevance of the duration of SD varies for different tumour types and grades. 
Therefore, it is highly recommended that the protocol specify the minimal time interval required 
between two measurements for determination of SD. This time interval should take into account 
the expected clinical benefit that such a status may bring to the population under study.  
 
Response review 
• 
For trials where the response rate is the primary endpoint it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the patients’ files and radiological images is the best approach.  
 
Reporting of results 
 
• 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). 
 
• 
All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered as failing to respond to 
treatment (disease progression).  Thus, an incorrect treatment schedule or drug administration 
does not result in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific. 
 
• 
All conclusions should be based on all eligible patients. 
 
• 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these subanalyses may 
not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported. 
 
• 
The 95% confidence intervals should be provided.