Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART):

Transcription

1 Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART): An international investigator-led phase III multi-arm multi-stage randomised controlled platform trial of adjuvant therapy in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse Sponsor: University College London Lead Trials Unit: Chief Investigator: Dr James Larkin Independent Scientific Peer Review and Funding: Kidney Cancer Educational Grant: AstraZeneca

2 Renal Cell Carcinoma Worldwide 13 th most common cancer 338,000 new cases reported in th most common cancer 12,523 new cases reported (2014) increase of 166% since late 1970s 4,421 deaths (2014) Current standard-of-care (SOC) for early RCC Surgery Radical or partial nephrectomy Global SOC after surgery Active monitoring Observation by clinical and radiological means Cancer Research, Accessed Dec 2017

3 Background and Rationale Currently no widely accepted adjuvant treatment ASSURE - negative DFS result S-TRAC - marginal DFS benefit PROTECT - negative DFS result Sunitinib, FDA approved in November Not currently felt to be practice changing in (NICE review?) Immunotherapies shown to improve outcomes in Advanced RCC Other tumour types

4 Background and Rationale Multiplicity of new agents Combination of treatments may be better than single-agent Multi Arm Multi Stage Being able to adapt to changes: adaptive trial design

5 MAMS Trial Design Multi-arm Test multiple relevant approaches Multi-arm, Multi-stage Multi-stage C T1 T2 T3 T4 Assess whether to continue to investigate an approach? Phase II Interim analyses Safety Lack-of-benefit Overwhelming benefit Successfully implemented in the STAMPEDE trial (Prostate Cancer) Phase III MKB Parmar et al. J Natl Cancer Inst 2008; 100:

6 Trial Schema Patients with confirmed RCC, high or intermediate (up to year 3 or 25%) Leibovich score eligible for randomisation into the study Randomisation Patients will initially be allocated in a ratio of 3:2:2 between arms A, B and C. Arm A active monitoring for 1 year Arm B durvalumab 1500mg q4w for 1 year Arm C durvalumab 1500mg q4w for 1y tremelimumab 75mg at day 1 and week 4 Arm D to be decided

7 Control Arm Current global SOC after nephrectomy for localised RCC is active monitoring Control arm Active monitoring Unblinded treatment (both IMPs are given as infusion) Active monitoring control will minimize burden to patients and healthcare system Some concerns raised about active monitoring as a control Might patients drop out of protocol follow-up if they know that they are not receiving active treatment? Since there are no alternative treatments known to be active in the adjuvant setting, nor a known rationale for delayed/late treatment after potentially curative surgery, we expect little drop out We will emphasize to all patients the importance of compliance with follow-up schedules, both from the perspective of optimizing their future care as well as to maximize the integrity of the trial

8 Intermediate and High-Risk Patients Clinically and ethically important to include patients from intermediate risk (IR) group Events from this group will take longer to accrue IR patients will be capped at 25% of the trial population Will contribute to the primary DFS analysis OS analysis will be in high-risk patients rationale is that competing causes of death in the IR group potentially large enough to dilute any treatment effect on OS

9 Primary Outcomes Co-primary outcome measures of DFS and OS OS analysis conditional on getting a signal in DFS Disease Free Survival Does treatment with either durvalumab alone or a combination of durvalumab and tremelimumab increase DFS compared with active monitoring? (Arms A vs B and A vs C respectively) Overall Survival Does treatment with either durvalumab alone or a combination of durvalumab and tremelimumab increase OS compared with active monitoring in patients classified as Leibovich high-risk? (Arms A vs B and A vs C respectively)

10 Trial Design Summary Design Patient Population MAMS To be initiated with 3 arms (4 th to be added) Incorporated in Statistical Analysis Plan Intermediate (for 3 years or 25% of accrual) High Risk Control Arm Contemporaneous, shared control arm alongside all research arms, current and future Can be changed Allocation Ratio 3 (Arm A): 2 (Arm B): 2 (Arm C)

11 Regulatory Submission Plans Proposed if DFS benefit observed License extension for durvalumab Pre-IND meetings with FDA and EMA Data collection and database CDISC compatibility Regulatory Submission Blinded independent review (if DFS positive) Prospective collection of CT scans Risk-based monitoring Central and statistical On site & scalable SDV Inspection and audit readiness

12 Milestones and Timelines Pre-IND Meeting FDA & EMA KC Review MHRA & HRA Submission Ethics and Regulatory Approval Jan-Feb 2017 Mar-2017 Oct-2017 Dec-2017

13 Summary: Why is RAMPART Important? 1 st academic-led adjuvant immunotherapy trial in current portfolio No adjuvant treatment for RCC Efficient trial design Platform for evolving research questions over the years International and multidisciplinary collaboration building on the SORCE trial Pharma collaboration If positive, it will provide earlier access to important new agents Inclusion of different risk cohorts over time Recognition that overall survival (OS) is a critical, long-term outcome measure Planned translational studies

14 RAMPART Trial Development Group James Larkin Royal Marsden Sarah Scovell Research Nurse Barts and the London Tom Powles Barts and the London Pat Hanlon Consumer Representative Paul Nathan Mount Vernon Christy Watson Consumer Representative Laurence Albiges Gustave Roussy France Max Parmar Senior Statistician Brian Rini Cleveland Clinic US Rick Kaplan Programme Lead Toni Choueiri Dana Farber Cancer Institute US Angela Meade Project Lead Ian Davis ANZUP Cancer Trials Group Australia Rahela Choudhury Clinical Project Manager Martin Stockler University of Sydney Australia Louise Choo Statistician David Harrison Pathologist University of St Andrews Francesca Schiavone Trial Manager Grant Stewart Urologist University of Cambridge Ben Smith Trial Manager Alastair Ritchie Urologist Nat Thorogood Data Manager Anita McWhirter Pharmacist Royal Marsden Kalam Hussain Data Manager