Eligibility, patient pathway & treatment Amy Campbell Clinical Trial Coordinator
Trial design Eligible patients consenting to OPTIMA 4500 patients 100 UK sites 4 years recruitment Randomisation 2250 2250 Group 1: Control Group 2: Test-directed Prosigna test High risk score (>60) Low risk score (<60) Randomisation blinded for chemotherapy assigned patients Chemotherapy Hormone therapy Chemotherapy Hormone therapy Hormone therapy
Primary outcomes Invasive disease free survival (IDFS): non-inferiority of testdirected chemotherapy treatment and endocrine therapy compared to chemotherapy followed by endocrine treatment Cost effectiveness evaluation of protocol specified multiparametric assay driven treatment against standard clinical practice.
Participant eligibility
Inclusion criteria Female or male, age 40. Excised invasive breast cancer. ER positive and HER2 negative. Axillary lymph node status of either: 1-9 involved. If 1-3 nodes at least one containing a macrometastasis (i.e. deposit >2mm in diameter) OR 1-3 lymph nodes involved with micrometastases only (i.e. a deposit >0.2-2mm in diameter) AND tumour size > 20mm OR Node negative with tumour size 30mm.
Inclusion criteria Bilateral and multiple ipsilateral cancers are permitted provided at least one tumour fulfils the entry criteria and none meet any of the exclusion criteria. Considered appropriate for adjuvant chemotherapy by treating physician. Fit to receive chemotherapy and other trial-specified treatments with no concomitant medical, psychiatric or social problems that might interfere with informed consent, treatment compliance or follow up. Written informed consent for the study.
Exclusion criteria X 10 involved axillary nodes or evidence for internal mammary node involvement. X ER negative OR HER2 positive/amplified. X Metastatic disease. X Previous diagnosis of malignancy unless: managed by surgical treatment only and disease free for 10 years basal cell carcinoma of skin or cervical intraepithelial neoplasia ductal carcinoma in situ (DCIS) of the breast treated with surgery only lobular carcinoma in situ (LCIS) or lobular neoplasia of the breast. X Use of HRT at the time of surgery.
Exclusion criteria X Pre-surgical chemotherapy, endocrine therapy or radiotherapy for breast cancer. X Commencement of adjuvant treatment prior to trial entry. X Trial entry more than 8 weeks after completion of breast cancer surgery. X Planned further surgery for breast cancer, including axillary surgery, to take place after randomisation, except either reexcision or completion mastectomy for close or positive/involved margins.
Participant pathway
Randomisation Confirm eligible. Obtain written informed consent. Patient completes baseline Patient Questionnaire Booklet (QoL and Health Resource Use). Plan chemotherapy From protocol permitted regimens If premenopausal, plan endocrine therapy Do you intend to treat with an AI or tamoxifen? Telephone the CTU Randomisation Service. You will be given a Participant Trial Number (4 digits). You won t be told which arm the patient is randomised to.
Diagnostic tissue blocks Following randomisation, send representative tissue block to central laboratory (target: 3 days). Pathologist to select a representative tissue block from the surgical resection (SOP provided). Bilateral or multiple ipsilateral cancers you may need to submit blocks from more than one tumour deposit. SOP provides guidance. If in doubt please ask!
Testing & treatment allocation TEST-DIRECTED ARM STANDARD/CONTROL ARM Central lab receives sample Central lab receives sample Sample assessed for invasive tumour content Sample assessed for invasive tumour content Prosigna test performed Sample stored Prosigna test results reported to OPTIMA trial office OPTIMA trial office notify site of participant s treatment allocation OPTIMA trial office notify site of participant s treatment allocation Time from randomisation to notification of treatment allocation is 2-4 weeks For patients allocated to chemotherapy, randomisation is blinded from sites
Understanding the treatment allocation timeline Weekly Prosigna test-run will start on Weds and finish on Fri Mon Tues Weds Thurs Fri Sat Sun Mon Tissue samples received at central lab by midday Weds will be included in that week s test run Treatment allocation will be sent to site on Fri pm or Mon: turnaround within 7 days Tissue samples received after midday Wed will be included in the following week s test run Held over to following week s run: turnaround within 14 days Other factors that may impact the timeline: Test failure (estimate 2%): repeat following week Additional tests required (ER, HER2 confirmation for tumours with non-luminal Prosigna subtype, estimate 4%)
Timeline in practice January March 2017 Calendar days from randomisation to treatment allocation Median of 9 days Range of 4 to 18 days
Treatment within OPTIMA
Surgery & radiotherapy Surgery Before trial entry (consent) appropriate surgery should be performed according to local guidelines. All axillary surgery must be completed before trial entry. Re-excision of margins or completion mastectomy permitted following trial entry. Radiotherapy Radiotherapy is given according to local practice. OPTIMA is compatible with POSNOC, but all planned axillary surgery must be completed prior to entry into OPTIMA.
Chemotherapy Chosen from a list of permitted regimens. Intended regimen must be stated at randomisation. Chemotherapy to be started within 2 weeks of treatment allocation. Monitoring during treatment is according to local guidelines. (F)EC75-80 (F)EC-T TC TAC PERMITTED REGIMENS (F)EC90-100 (F)EC-Pw E-CMF Dose dense AC/EC-P
Hormone therapy Hormone therapy is to be started no later than: 2 weeks from treatment allocation in patients assigned to no chemotherapy 4 weeks after day 1 of the final cycle of chemotherapy for all other patients The hormone therapy a participant is given is based on the patient s gender and for women their menopausal status at the time of trial entry (i.e. consent) The recommended duration of endocrine therapy is 10 years for all patients.
Hormone therapy Initial treatment period (years 0-5) Male: Tamoxifen Postmenopausal at trial entry: Aromatase inhibitor. Tamoxifen may be given where there is a contraindication to aromatase inhibitor therapy. Premenopausal at trial entry: Tamoxifen or an aromatase inhibitor. Ovarian suppression - either with a Gonadotropin-releasing hormone (GnRH) agonist, such as goserelin 3.6mg subcutaneously once a month for at least 3 years, or by bilateral surgical oophorectomy.
Hormone therapy Extended treatment period (years 6-10) All patients are advised extended adjuvant endocrine therapy for a further 5 years to a total of 10 years as follows: Male: Tamoxifen Female: Aromatase inhibitor or tamoxifen For women who were deemed premenopausal at trial entry, if considering switching from tamoxifen to an aromatase inhibitor at 5 years, the patient s menopausal status needs to be confirmed at this stage as postmenopausal.
Adjuvant bisphosphonates Recommend that patients in the OPTIMA trial receive a bisphosphonate (oral or intravenous) for 2-5 years. To avoid potential treatment imbalance, sites should ensure bisphosphonate treatment is the same for all patients irrespective of whether the patient is receiving chemotherapy or not.
Where we are today
Sites & recruitment Opened 16 th January 46 sites open to recruitment 28 sites in active set-up 41 patients randomised Targets for end of April No. of open sites: 40 No. of patients randomised: 71 Open sites Addenbrooke's Hospital Barnet Hospital Basingstoke and North Hampshire Hospital Beatson West of Scotland Cancer Centre Bedford Hospital Birmingham City Hospital Blackpool Victoria Hospital Chase Farm Hospital Derriford Hospital, Plymouth Dumfries and Galloway Royal Infirmary Glan Clwyd Hospital, Bodelwyddan Hairmyres Hospital Hinchingbrooke Hospital Inverclyde Royal Hospital Lister Hospital Luton and Dunstable University Hospital Macclesfield District Hospital Mount Vernon Hospital Norfolk & Norwich University Hospital North Tees and Hartlepool NHS FT Nottingham University Hospital Pennine Acute Hospitals Queen Elizabeth Hospital Gateshead Queens Hospital, Burton On Trent Royal Albert Edward Infirmary, Wigan Royal Alexandra Hospital, Paisley Royal Cornwall Hospital Royal Devon and Exeter Hospital Royal Free Hospital Royal Hampshire County Hospital Russells Hall Hospital, Dudley Salisbury District Hospital Scarborough Hospital Singleton Hospital, Swansea St Mary's Hospital, Isle of Wight Sunderland Royal Hospital Torbay Hospital University College London Hospital University Hospital Coventry University Hospitals of North Midlands Western General Hospital, Edinburgh Whittington Hospital Wishaw General Hospital Wrexham Maelor Hospital, Wrexham York Hospital Ysbyty Gwynedd, Bangor