Mid-recruitment trial redesign to incorporate genetic sub-types: the PICCOLO Trial

Transcription

1 Mid-recruitment trial redesign to incorporate genetic sub-types: the PICCOLO Trial Sarah Brown Catherine Olivier On behalf of the PICCOLO Trial Team Society for Clinical Trials May 15-18, 2011 Vancouver, Canada

2 Overview PICCOLO was originally designed in 2006 however after new molecular data emerged in 2008 a redesign was necessary This new data presented a number of challenges - Urgent Safety Measure Trial Redesign Protocol Amendment Acceptance and implementation of new design at trial sites Implementation at CTRU Initiation of prospective molecular testing service

3 PICCOLO Original Trial Design Multicentre, phase III, chemotherapy trial in advanced colorectal cancer, academically led with industry financial support n = 1269 IrCs irinotecan + ciclosporin Ir irinotecan alone IrPan irinotecan + panitumumab Ir vs IrCs non-inferior efficacy primary endpoint PFS at 12 wks Ir vs IrPan superior efficacy primary endpoint OS

4 New Molecular Data Data released at the ASCO meeting in Chicago (30 May - 03 June 2008) Showed beyond reasonable doubt that patients with K-RAS mutated colorectal cancer do not benefit from the addition of anti- EGFR monoclonal antibodies (cetuximab or panitumumab) to their chemotherapy. Consequences for PICCOLO Only patients with a K-RAS wild-type tumour receiving irinotecan plus panitumumab (IrPan) stand to benefit.

5 How did we react? 30 th May 3 rd June American Society for Clinical Oncology Conference 4 th June CI returns from ASCO. Internal discussion with TMG 9th June DMEC agrees to Urgent Safety Measure and new protocol design 24hour automated randomisation service suspended 10 th June Urgent safety measure implemented

6 What is an Urgent Safety Measure? Regulation 30. in the The Medicines for Human Use (Clinical Trials) Regulations 2004 (amended 2006) (1) The sponsor and investigator may take appropriate urgent safety measures in order to protect the subjects of a clinical trial against any immediate hazard to their health or safety. (2) If measures are taken pursuant to paragraph (1), the sponsor shall immediately, and in any event no later than 3 days from the date the measures are taken, give written notice to the licensing authority and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures.

7 Urgent Safety Measure Office hours (9am 5pm) telephone paper randomisation implemented Allowed only patients with known KRAS- wt to be randomised to IrPan No action thought to be necessary for patients with KRAS mutant tumours already receiving Pan (Pan shown to have no benefit in these patients rather than cause harm) All trial sites urgently notified of changes

8 Trial Re-design n = 1324 KRAS mutated or unknown KRAS-wt (c.12/13 & 61) IrCs irinotecan + c sporin Ir irinotecan alone Ir irinotecan alone IrPan irinotecan + pan mab Ir vs IrCs non-inferior efficacy primary endpoint PFS at 12 wks Ir vs IrPan superior efficacy primary endpoint OS

9 Protocol Amendment Action: Substantial amendment to protocol and PIS Challenge: Day-to-day trial management still needed KRAS specific consent required New registration process prior to randomisation New system required additional testing TMG review & approval Protocol implemented from October2008 Time pressures IMPACT: More man-power needed

10 Implementation of new design at trial sites Action: Acceptance of new design Local approvals Keep centres informed /training Challenge: Not all study sites liked the new trial design (in particular not releasing KRAS status) Concern re delaying tmt Can be a lengthy process Teething problems with new protocol and KRAS testing IMPACT: Knock on effect on recruitment

11 Implementation at CTRU Action: Changes to CRFs to capture new data New administrative systems for central KRAS testing Change to randomisation system including registration Challenge: Knock on effect on database consider data collected for patients under original protocol Test, implement and maintain new system Ongoing queries from sites re KRAS status IMPACT: Day-to-day management of trial man-power

12 Initiation of prospective molecular testing service Action: Consenting to KRAS testing Challenge: Time between patient identification and trial entry Obtaining pathology blocks Performing KRAS testing Obtaining results for randomisation Delays at trial site when expediting tissue Failed tests need retesting Time between patient registration and randomisation IMPACT: Day-to-day management of trial Increased communication with sites & central lab

13 Dec-06 Jan-07 Feb-07 Mar-07 Apr-07 May-07 Jun-07 Jul-07 Aug-07 Sep-07 Oct-07 Nov-07 Dec-07 Jan-08 Feb-08 Mar-08 Apr-08 May-08 Jun-08 Jul-08 Aug-08 Sep-08 Oct-08 Nov-08 Dec-08 Jan-09 Feb-09 Mar-09 Apr-09 May-09 Jun-09 Jul-09 Aug-09 Sep-09 Oct-09 Nov-09 Dec-09 Jan-10 Feb-10 Mar-10 Apr-10 May-10 Jun-10 Jul-10 Aug-10 Monthly recruitment Cumulative recruitment Effect on recruitment Monthly recruitment Cumulative recruitment Target recruitment Opened to recruitment: 04/12/ As of 01/09/10 actual pts: ` cent New sites initiated and opened Negotiated extension with pharma partner and with CTAAC Continuous updates via trial newsletters

14 Points for Consideration Trials requiring a mid-recruitment redesign may become more common as further genetic advances are made Consider prospectively requesting consent for tumour collection Be realistic about manpower required for protocol writing and designing new systems will affect regular trial activities Give ample training in new design, to ALL departments involved Minimise time between registration and randomisation consider allowing testing in advance Make only minimal changes to CRF knock on effect on database Easy identification of patients recruited under different versions of protocol (e.g. trial number) Consider any changes required to monitoring plan

15 Thank you Any questions? Acknowledgements: