Award Title: CRUK/22/005: Relapsed Follicular lymphoma Randomised trial Against standard ChemoTherapy (REFRACT): A randomised phase II trial of investigator choice standard salvage immuno-chemotherapy versus sequential novel therapy experimental arms
Funder: Cancer Research UK

Abstract: Background:
Follicular lymphoma (FL) is a common subtype of non-Hodgkin lymphoma with an estimated 10-year UK prevalence of 16,000 cases. Most patients have incurable, advanced stage disease that follows a long relapsing/remitting course (rrFL) with progressively shorter remissions despite multiple lines of therapy. Treatment resistance, early progression, and poor survival occurs in 20-25%, whilst increasing numbers experience cumulative complications or treatment resistance after multiple therapies, and eventually exhaust treatment options. Treatment resistance underpins the need for novel therapies and a deeper understanding of the biological determinants of response/resistance to develop personalised approaches. There are no standard treatment pathways, no randomised trials comparing experimental with current therapies, and limited outcome data from current therapy in rrFL. This has created immense difficulties around therapy choice and approval of novel agents. Randomised trials are urgently needed to identify the value of novel agents in treatment pathways.

Aims:
1.Identify novel therapies with superior efficacy versus standard treatment based on complete metabolic response (CMR) rates.
2.Identify novel therapies with high efficacy in high-risk FL.
3.Identify therapies with other advantages over standard treatment e.g., safety, quality of life.
4.Prospectively evaluate outcomes for current immunochemotherapy treatment to provide new benchmarks.
5.Evaluate the prognostic value of calculating total metabolic tumour volume via positron emission tomography (PET)-computed tomography (CT) imaging for future risk-adapted treatment approaches.
6.Identify predictive and dynamic biological determinants of treatment response and resistance in FL, including high-risk FL, using advanced molecular techniques.

Methods:
REFRACT is a prospective, randomised, phase ll platform trial for sequential evaluation of experimental versus standard treatments for rrFL, with embedded translational research into the pathobiology of rrFL. There are 3 treatment rounds; each has a control arm of investigator choice immuno-chemotherapy and an experimental novel treatment arm. Randomisation is 1:1 (experimental:control) in round 1 and 4:1 (experimental:control) in rounds 2 and 3 as the final analysis will use pooled control arm data. This design minimises patient numbers allowing accelerated trial delivery whilst maintaining randomisation to prevent selection bias. 

Results will be used to:
1.Accelerate onward development of promising novel agents;
2.Inform future trials, treatment pathways, guidelines, and regulatory approvals with unique clarity on the value and place of novel agents and contemporary outcome data for standard immunochemotherapies;
3.Develop novel biomarkers and gain new insights into the pathobiology of treatment response and resistance, and;
4.Provide an efficient trial platform for ongoing comparative evaluation of novel therapies.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS