BriTROC1 Study

Sample Collection Study to Investigate the Role of Homologous Recombination Deficiency in

Platinum Sensitivity in Recurrent high Grade Serous Ovarian Cancer

(Version 5, 12th November 2014

Study Organisation

• Sponsored (Research Governance) - Greater Glasgow and Clyde Health Board (GGCHB)

• Coordinated by CR-UK Clinical Trials Unit in Glasgow

• CR-UK CTU Glasgow are responsible for setting up, the day-to-day running and statistical analyses of study data

• Chief Investigator is Professor Iain McNeish, The Beatson West of Scotland Cancer Centre (BWoSCC)

Study Team

CRUK CTU Team

– Chief Investigator: Professor Iain McNeish / Dr James Brenton

– Trial Statistician: Jim Paul

– Project Management: Liz-Anne Lewsley

– Clinical Trial Co-ordinator: Calum Innes

– Laboratory Contact: Darren Ennis

– Computer Programmer: Stephen Clark

– Clinical Trial Monitor: Eileen Smillie

Study Summary

• Multi-centre, open, non-randomised study.

• Study recruitment: 300 biopsies/samples (8 sites in the UK) over 3 years.

• Study population: 100 patients with platinum-resistant relapsed HGSOC, 200 patients with platinum-sensitive relapsed HGSOC.

• Timelines:

- Start date December 2012 - Planned accrual completion is December 2015

Study Objectives

• To demonstrate the safety and feasibility of acquiring tumour biopsies from women with relapsed ovarian cancer in multiple centres.

• To obtain 300 biopsies from women with relapsed high-grade serous ovarian cancer - 100 in platinum-resistant disease (relapse within 6 months of platinum-based chemotherapy) and 200 in platinum-sensitive disease (relapse 6 months or more since platinum-based chemotherapy).

• To assess Homologous Recombination Deficiency (HRD) genes in relapsed High Grade Serous Ovarian Cancer (HGSOC) compared with the same genes in tumours at first presentation.

• To compare HRD genes in relapse platinum-sensitive HGSOC with the same HRD genes in relapse platinum-resistant HGSOC. .

Study Endpoints

Primary endpoint• To obtain 300 fit-for purpose imaging-guided biopsies from women with relapsed high grade

serous ovarian cancer – 100 from women with platinum-resistant relapse (relapse within 6 months of platinum-based chemotherapy) and 200 from women with platinum-sensitive relapse (relapse 6 months or more after completion of platinum-based chemotherapy).

Secondary endpoints• Assessment of mutations in HRD genes, BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, in

relapsed HGSOC samples by targeted sequencing.

• Comparison of allelic ratio of BRCA1 and BRCA2 in relapsed HGSOC and archival tumour samples taken at the time of diagnosis.

• Analysis of mutations in TP53 (positive control for high grade serous pathology), PTEN, APC, BRAF, KRAS, PIK3CA in relapsed HGSOC and archival tumour samples.

• Assessment of germline DNA mutations in BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 in women with relapsed HGSOC.

• Assessment of methylation of BRCA1 and BRCA2 in relapsed HGSOC and archival tumour samples taken at the time of diagnosis.

Patient RegistrationProcedure for all sites

• Check that patient has given written informed consent

• Check that patient fulfils eligibility criteria

• Complete Registration Form

• PHONE or FAX registration details to the CRUK CTU Registration Service

• Each patient registered will be allocated a unique trial number (3-digits)

• Please note that registration must take place prior to any study specific procedures being performed

Registration Service

CRUK CTU Glasgow registration service:

Tel: 0141 301 7234 Fax: 0141 301 7228*

08:30 –17:00 Mon–Thurs, 08.30-16.30 Friday (except public holidays)

*Faxes received outside of office hours will be processed the next working day

Site Set-up

CRUK CTU Glasgow is responsible for:

• Main REC Approval• Overall Sponsor Approval• Site initiation calls• Transfer of SSI to site• Providing all essential documentation to site for local submission• Investigator Site File

Site Responsibilities (a pre-activation checklist is provided to sites):

• Staff Contacts & Responsibilities Sheets• SSI submission/R&D Approval• Investigator/site staff CVs • Participating Site Agreement• PIS/Consent/GP letter on local headed paper

Inclusion Criteria• Patients with recurrent histologically-proven ovarian cancer, primary peritoneal carcinoma or

fallopian tube cancer of high grade serous and high grade endometrioid subtypes. Patients who have had a diagnosis of ovarian cancer with a known germline mutation in BRCA1 and BRCA2 will also be eligible for inclusion regardless of histological subtype. Patient’s who are havin a diagnostic image-guided biopsy may be consented and study biopsy taken while awaiting pathological review. Eligible patients who have had samples collected under generic research consent may be registered retrospectively only after full discussion with the site, Chief Investigator and CR-UK CTU (and BriTROC-1 specific consent obtained).

• Patients must have received at least one line of platinum-containing chemotherapy• Availability of formalin-fixed, paraffin-embedded tissue taken at the time of original diagnosis

of high grade serous ovarian cancer. This may be primary surgical debulking specimen OR core biopsy. For those with only a core biopsy from time of diagnosis, availability of specimen taken at interval debulking surgery is desirable, but not essential.

• Patients must have disease deemed suitable for imaging-guided biopsy (ultrasound or CT) by an experienced radiologist or suitable for intra-operative biopsy during secondary debulking surgery as determined by an experienced gynaecological oncology surgeon. Other biopsies, such as skin deposits, are also acceptable. However this must be confirmed with the Cancer Research UK Clinical Trials Unit prior to patient registration.

• Age ≥ 18 years.• Written informed consent.• Able to apply with study procedures.• Life expectancy > 3 months• No contraindication to biopsy as appropriate.

Exclusion Criteria

• Ovarian, primary peritoneal or fallopian tube cancer of low grade serous, grades 1 or 2 endometrioid, clear cell or carcinosarcoma/MMMT subtypes unless associated with known germline mutation in BRCA1 ro BRCA2

• Borderline/low malignant potential tumours• Any non-epithelial ovarian malignancy• Patients with asymptomatic rising CA125 with no radiological evidence of

recurrent ovarian cancer.• Original diagnosis of high grade serous cancer made on cytology only

Informed Consent Process-1

• Two original Consent Forms must be completed by a clinician (or deputy listed on Staff Contacts & Responsibilities Sheet)

• Two originals signed and completed by the patient

• Date must be on or prior to registration

• Make one photocopy

- Original to be filed in Investigator File - Original to be given to patient (+PIS) - Photocopy to be filed in hospital notes

• Consent Form must not be sent to the CRUK CTU

Informed Consent Process-2

• Errors noticed after consent - Add explanatory note/file note

• New version of Patient Information Sheet must be provided to patients consented with previous version if this is required by Sponsor

- Give to all patients regardless of treatment stage either by post or during clinic visit if this is required by Sponsor

• Patients who are still on study will be required to repeat the consent process using the updated form if this is required by Sponsor

• If not appropriate to re-consent patient (i.e. patient terminally ill) make a note on the re-consenting log

Case Report Forms (CRFs)

• Registration Form

• Baseline/Image Guided Biopsy Form

• Study Related Complications Form

• Follow Up Form

• Consent Withdrawal Form

• 2nd Biopsy Registration Form

• Study Related Complications Form

• 2nd Image Guided Biopsy Form

Study Related Complications Expedited Reporting

• The protocol requires that the complication rate is assessed. All significant study-related complications will be monitored continuously. Significant complications will be notified immediately to the CTU, allowing continuous supervision.

• For > Grade 2 events of post image guided biopsy:

– Pain– Post operative haemorrhage– Wound infection– Peritoneal infection

• The Study Related Complications Expedited Reporting Form should be completed and faxed within 24 hours of first becoming aware of the event

• These are ONLY for events related to image guided biopsy

• Once received by the Clinical Trial Co-ordinator, this will be passed to the Study Statistician

• The complication rate will be assessed for the study as a whole and also at individual sites

• If the complication rate at an individual site is high the centre involved will be suspended until a detailed review of the cases has taken place by the Trials Management Group

CRF Completion

• Black ball-point pen

• Correction fluid etc. must not be used

• Errors crossed out with a single stroke, correction inserted and change initialled and dated

• An explanation can be written next to amendment if necessary

• Date format: DD / MON / YYYY

• Information on CRFs must be verifiable in source documents

• Take photocopy of all completed CRFs

• Original to CRUK CTU Glasgow

• CRF completion guidelines will be supplied

Consent Withdrawal

• This is when the patient specifically asks to withdraw their consent at any point in the study

• Ensure that the level of consent withdrawal is clearly documented in the source data

• If this occurs:– Document clearly in the patient notes that the patient has

withdrawn consent, the level of consent withdrawal and the reason (if the patient has given any);

– Complete the consent withdrawal notification form ;– Send the consent withdrawal notification form to the CR-UK CTU– No further follow-up should be collected on the patient from that

point onwards

• The CTU will have a system in place for destruction of samples should this be necessary dependant on the level of consent withdrawal

Samples and Sample CollectionImage-guided Tumour Biopsies

• Two 14-18G cores of tissues as free from normal tissue as possible

• Further details on sample shipment and handling are contained in the Laboratory Manual

• Samples should be posted immediately to the Analytical Services Unit, University of Glasgow

Patients who experience further disease progression following treatment with platinum-containing chemotherapy whilst the BriTROC1 study is still active may be asked to undergo a second biopsy. This is not compulsory and patients will have consented to this at the time of original study entry.

It is important that the 2nd Biopsy Registration Form is completed and the CRUK CTU contacted prior the 2nd biopsy being undertaken

Samples and Sample CollectionFormalin Fixed Blocks

• Formalin-fixed, paraffin-embedded tissue must be available

• Tumour tissue taken at the time of original diagnosis will be retrieved

• One block of tissue as free from normal tissue as possible will be removed

• The original pathology report confirming high grade serous or high grade endometrioid histology must be available

• A panel of suitable immunohistochemistry (e.g CK7, CK20, WT1) pathology must have been done. For patients with other histological subtypes associated with germline mutations in BRCA1 or BRCA2, formal evidence of the mutation must be provided

• Frozen material from the time of original diagnosis if available alongside FFPE

• Further details on sample shipment and handling are contained in the Laboratory Manual

Samples and Sample CollectionBlood Samples

• On the same day (or up to 72 hours prior to) imaging-guided biopsy, up to 20ml whole blood will be collected in EDTA tubes and stored at -800C. In addition, 20ml blood will be collected, clotted on ice, centrifuged and plasma stored at -800C

• Of the whole blood taken, 10ml may be retained in case patients request referral to a clinical geneticist (if local practice allows testing of previously stored samples) in a previously undiagnosed germline mutation in BRCA1 or BRCA2 is identified in laboratory analyses. However, this sample need not be taken if local practice demands that a new sample be taken immediately prior to formal mutation analysis.

• For patients known to have germline BRCA1 or BRCA2 mutations, formal evidence of mutation status should be sent to the CR-UK Clinical Trials Unit.

• In addition, a further optional 10ml blood will be collected for plasma storage, prior to both first and second cycles of chemotherapy following biopsy. Samples should be collected no more than 72hrs prior to administration of chemotherapy

• Further details on sample shipment and handling are contained in the Laboratory Manual

Patients who experience further disease progression following treatment with platinum-containing chemotherapy whilst the BriTROC1 study is still active may be asked to undergo a second biopsy. This is not compulsory and patients will have consented to this at the time of original study entry. If this is the case then a further set of blood samples (as above) will be taken.

Samples and Sample CollectionAscites Sampling

• Only sites in Glasgow and Cambridge participating in ascites collection for this study

• If patients have symptomatic ascites at time of biopsy, and it is deemed clinically appropriate, ascites should be drained

• Where facilities are available to culture primary ascites:

– 400ml of ascitic fluid will be centrifuged– Ascites fluid will be removed and stored in 50ml aliquots at -800C– Cell pellet will be resuspended in 10 ml warm RPMI medium and divided

between 5 x 75cm2 tissue culture flasks and fed with a further 15 ml RPMI medium supplemented with 15% autologous ascitic fluid

• Further details on sample shipment and handling are contained in the Laboratory Manual

Samples and Sample Collection

• Consumables as detailed in the Lab Manual will be provided

• Samples will be labelled with the patient’s trial no, initials, and the timepoint, date and time the sample was taken

• Collection will be transferred to the Analytical Services Unit, Institute of Cancer Sciences, University of Glasgow, at regular intervals

• Further details are contained in the Laboratory Manual

Quality Assurance• Trial Investigators and Site Staff must ensure that the trial is conducted in compliance with the

protocol, Research Governance Framework 2006 (as amended) and the principles of Good Clinical Practice (GCP) and the applicable regulatory requirements.

• Limited on-site and telephone monitoring will be performed by the Sponsor. Central monitoring of trial data will also be performed by the Study Statistician and the Clinical Trial Co-ordinator. The Sponsor reserves the right to conduct for-cause monitoring visits or audits in the event of non-compliance with the trial protocol.

• The CTU will control data consistency and data quality by entering trial data onto the CTU trial database. Computerised and manual consistency checks will be performed and queries issued in cases of inconsistency or missing information. A full audit trail of any changes to the database will be maintained.

• The Trial Management Group will ensure the study is being managed according to protocol, Research Governance Framework 2006 (as amended) and the principles of Good Clinical Practice (GCP) and the applicable regulatory requirements.

• Assays of biological objective that are primary or secondary endpoints will use Study Plans and Standard Operating Procedures agreed by the Trial Management Group.

• Study plans for tertiary endpoints will be proposed by Investigators to the Trial Management Group for approval to ensure optimal use of samples and co-ordination of studies.

Ethical and Regulatory Standards

• This study conducted in adherence to Research Governance Framework 2006 (as amended) and the principles of GCP

• This study is carried out in accordance with the World Medical Association Declaration of Helsinki 2008

Contact Details

CR-UK CTU, GlasgowCancer Research UK Clinical Trials Unit

Level 0Beatson West of Scotland Cancer Centre

1053 Great Western RoadGlasgow, G12 0YN

Tel: +44(0) 141 301 7234Fax: +44(0) 141 301 7228

Calum Innes Liz-Anne LewsleyClinical Trial Co-ordinator Project ManagerCalum.innes@glasgow.ac.uk liz-anne.lewsley@glasgow.ac.uk