1. The Synergism or Long Duration (SOLD) Study
A randomised phase III study comparing trastuzumab plus docetaxel (HT) followed by 5-FU, epirubicin, and cyclophosphamide (FEC) to the same regimen followed by single-agent trastuzumab as adjuvant treatments for early breast cancer

2. Beatson West of Scotland Cancer Centre
UK Chief Investigator
Dr Judith Fraser
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow G12 0YN
Tel:

3. Study Chief Investigator
Professor Heikki Joensuu
Clinical Research Institute Helsinki University Central Hospital Ltd
PL 700
(Haartmaninkatu 8/Biomedicum Helsinki) FIN HUS
Finland

4. Study Sponsor The Finnish Breast Cancer Group
Clinical Research Institute Helsinki University Central Hospital Ltd
PL 700
(Haartmaninkatu 8/Biomedicum Helsinki) FIN HUS
Finland

5. UK Sponsors Representative
Greater Glasgow and Clyde NHS Board

6. Clinical Trial Co-ordinator
UK Study Team - Glasgow
Project Manager
Liz-Anne Lewsley,
Clinical Trial Co-ordinator
Diann Taggart,
Study Monitor
Jan Graham,

7. SOLD Population
Female patients with HER2+ breast cancer with no overt distant metastases, and who are considered to have a high risk of breast cancer recurrence

8. SOLD Design RANDOMIZE In both Arms:
Docetaxel 80/100 mg/m2
FE75C
3-weekly trastuzumab (H)
RANDOMIZE
In both Arms:
RT (according to the institutional practise)
Endocrine therapy for a minimum of 5 yrs when ER/PgR +ve
H for 9 wks
H for 9 wks
H to complete 1 year
(14 3-wkly infusions)

9. Treatment Regimens Arm A HT x 3 → FEC75 x 3
Herceptin (H) administered either weekly or 3-weekly
Either the weekly or the 3-weekly schedule should be used consistently throughout the study
Weekly: First dose 4 mg/kg, subsequent doses 2 mg/kg
3-weekly: First dose 8 mg/kg, subsequent doses 6 mg/kg
Herceptin infused prior to docetaxel (T). If T administration needs to be deferred, H administration will also be deferred
Docetaxel doses must be consistent, either 100mg/m² or 80mg/m² in all patients, adjustments can only be made for age
G-CSF and dose reductions allowed

10. Arm B
HT x 3 → FEC75 x 3 → H (3 wkly) x 14
Chemotherapy as in Arm A
Single-agent H after chemo: 3-weekly - first dose 8 mg/kg, subsequent doses 6 mg/kg

11. SOLD Objectives Primary Secondary: DFS Overall survival (OS)
Distant disease-free survival (DDFS)
Cardiac disease-free survival (CDFS)
LVEFs
Safety and toxicity
QoL (EuroQol EQ-5D)
Collection of biological samples (tumour, serum)

12. Key Inclusion Criteria
HER2+ invasive BC
Assessed with CISH or FISH
If not available IHC+++
A high risk of recurrence with either
N0 with the longest invasive tumour diameter >5mm and histology grade >2
>10mm histological grade irrelevant
Histologically confirmed node+ disease
Please refer to protocol for full list of inclusion criteria

13. Key Exclusion Criteria
Presence of distant metastases
Inflammatory breast cancer
Clinically significant cardiac disease
LVEF <50% (either ultrasound or MUGA)
Neoadjuvant chemotherapy
WHO performance status >1
>12 weeks between breast surgery and randomisation
Prior malignancy within the past 5 years, except basal cell carcinoma or carcinoma in situ of the uterine cervix
Pre-existing motor or sensory neurotoxicity of > grade 2, unless related to mechanical etiology
Please refer to the protocol for a full list of exclusion criteria

14. Randomisation Randomisation for the study is web based
If website down for any reason, randomisation performed via fax:
Patients are stratified on the following variables
no. of +ve nodes
HER2 assessment method
Centre
ER positivity

15. Study Website https://www.ctru.auckland.ac.nz/sold/
Username and password required
Once site receives all necessary approvals application for username and password will be issued
Key study documents can be found and downloaded from the website – CRFs, SOPs, QoLs, SAE forms, CIOMS forms etc
Recruitment reports can be generated on the site allowing tracking of accrual
Do Not use the patient information sheet from the website as we have our own ethics approved UK version

16. RT and Endocrine Therapy
Radiotherapy
should be administered according to local practice (mandatory following breast conserving surgery)
Recommended to be started within 2 months of completion of chemotherapy
Hormonal therapy
When cancer ER and/or PR positive
Choice of therapy at clinicians discretion
Administered for a minimum duration of 5 yrs
Recommended to be started within 3 months of completion of chemotherapy

17. SOLD Patient Numbers Planned sample size: 3,000 worldwide
from the UK
1st patient recruited into study January 2008
1809 patients recruited to end of July 2013, 282 recruited UK (8 England, 274 Scotland) from March 2009
Recruitment expected to last until end of 2015

18. SOLD Recruiting Countries
Belgium
Brazil
Finland
Germany
Iceland
Italy
Korea
Netherlands
Serbia
Sweden
New Zealand
United Kingdom

19. Safety SAEs/SUSARs graded according to CTCAE v 3.0
SAEs/SUSARs also evaluated during the single-agent trastuzumab phase in both arms
SAEs/SUSARs should be reported by fax to the SOLD Study in Helsinki, Finland

20. Safety
SOLD Study Centre are responsible for deciding on SUSAR status and providing SUSAR reports
Dr Fraser, as CI for UK, is then responsible for reporting SUSARs to MHRA, Main REC, and participating sites in the UK
Dr Fraser is also responsible for submitting the Development Safety Update Reports (DSURs), (prepared by the Finnish Breast Group), to MHRA, Main REC, and participating sites in the UK

21. Patient Safety Evaluations
LVEF monitoring with either echo or MUGA
Baseline method should be consistent throughout per patient
measured 6 times (baseline, weeks 18, 31, 43, 61, and at 3 years)

22. Research Blood Samples
2ml serum and 2ml plasma (baseline, week 61, then annually)
Collection optional for patient
Should be stored at least -20
Only study specific labels will be supplied by the Sponsor, all tubes from stock

23. Transportation of Serum and Plasma Samples
Samples should be shipped on dry ice directly to the Study Centre in Finland
Professor Heikki Joensuu
Department of Oncology
Helsinki University Central Hospital Haartmaninkatu 4
P.O.Box 180
FIN Helsinki, Finland
An should be sent to Mia Viskari with a copy to Prof Joensuu advising that samples have been shipped. Please see shipping and handling instructions in the Investigator Site File for courier details etc.

24. Tumour Samples Paraffin embeded tissue block
gene amplifications, mutations, signalling proteins
Again, collection optional for patient
Will be used for quality control of HER2 assessment
Samples should be sent via mail to Study Centre in Helsinki, Finland (as previous). Please see shipping and handling instructions in the Investigator Site for further details

25. Pharmacy
All drugs to be taken from pharmacy stock, no special supply arrangements
A pharmacy file will be provided with accountability logs etc
An IMP Management Document will be supplied

26. Doses and Administration
Docetaxel, 5-FU, Epirubicin and Cyclophosphamide doses are calculated per BSA
Herceptin dose calculated /kg
Dose adjustments for weight only to be made where there is a difference of 10% to that of the baseline weight
Protocol states that FEC administration should be IV, have confirmation from CI that bolus is acceptable should this be normal practice.

27. Dose Banding If dose banded products are used as IMPs:
The dose banded product must be routinely used within the Trust/Board for the treatment of patients receiving standard therapy, i.e., outwith a clinical trial
The dose banded product must not be purchased or obtained by pharmacy specifically for use within the study. Instead, it must be procured as part of routine pharmacy stock
Dose banded products to be used in the study must be labelled as per section study procedures only in response to an individual patient prescription
There must be formal agreements in place between the Board/Trust and the supplier to ensure the product is of an appropriate quality; this may include local or national purchasing contracts
The supplier of the dose banded chemotherapy must maintain an adequate audit trail that would permit the batch number of the original product and diluent to be traced should this be required
The batch number, manufacturer and supplier of any dose banded drugs must be recorded by pharmacy for every dose used within the clinical trial

28. Monitoring The study will be monitored by the CR-UK CTU in Glasgow.
Each site will be visited at least once during study participation, again prior to interim analysis and again prior to final analysis.
100% of patients will have consent monitored.
A minimum of 50% of patients will be monitored for a selection of key fields.
It is important that case notes have as much information as possible contained within them to enable Source Data Verification
Monitor will not remove CRF pages, these should be sent directly to Study Centre in Finland.

29. Thank You
Thank you for your time, if you have any questions please detail these on your Investigator Initiation Presentation Acknowledgement when it is returned, or contact one of the following:
UK CI - Dr Judith Fraser
CTC – Diann Taggart
PM – Liz-Anne Lewsley