The aim of the REFRACT clinical trial is to find new therapies with improved outcomes compared to the current standard treatment available, in patients with relapsed or refractory follicular lymphoma. This will be done by comparing patients who have received a new treatment against patients who receive standard treatment based on their response to the treatment received.

In the REFRACT trial patients with relapsed or refractory follicular lymphoma (rrFL) will be randomised (randomly allocated) to receive a new treatment (experimental treatment) or standard treatment which will be chosen by their doctor prior to entering the trial (called investigator choice standard therapy (ICT)). There are 3 treatment rounds which will happen one after another, testing 3 different experimental treatments. The experimental treatment in each round will be compared to ICT. ICT will be a choice of 1 of 5 standard treatment options including RCHOP, RCVP, lenalidomide and rituximab, bendamustine and rituximab or obinutuzumab and bendamustine. Patients in Round 1 (R1) will be randomised using a 1:1 allocation ratio (meaning patients have a 50/50 chance of receiving the experimental treatment). In Round 1 the experimental treatment is epcoritamab combined with lenalidomide. Patients randomised to epcoritamab and lenalidomide will receive up to 12 28-day cycles of therapy; epcoritamab will be delivered as a subcutaneous injection weekly for cycles 1 and 2 and on day 1 of cycles 3-12. Lenalidomide will be taken orally on days 1-21 of each cycle. Patients in Rounds 2 (R2) and 3 (R3) (experimental treatments yet to be determined) will be randomised using a 1:4 allocation ratio in favour of the experimental treatment (meaning patients are more likely to receive the experimental treatment). The study will recruit 284 patients with rrFL over 5 years. The aim is to identify new therapies which have better outcomes compared to ICT based on patients response to treatment (tested by PET scan) after 24 weeks of therapy. Following treatment patients will be followed up yearly until the end of the trial (up to 10 years).

Inclusion Criteria:

1. Biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma (biopsy within 3 months of trial entry)
2. Aged 18 years or over
3. Advanced disease that in the opinion of the treating physician requires treatment
4. Patient suitable for standard available therapy at the Investigator's discretion
5. Prior therapy with at least one line of immunochemotherapy. Previous radiotherapy at any time is permitted and will not count as a line of therapy. Previous rituximab monotherapy is also permitted as long as patients have at any time also received at least one line of immunochemotherapy
6. Assessable disease by PET-CT (at least one involved node with long diameter >1.5cm, or extranodal lesion >1cm )
7. ECOG performance status of 0, 1 or 2 at trial entry
8. Adequate organ function defined as; i. ANC ≥ 1.0 x 109/L (growth factor use is permitted) ii. Platelet count ≥ 75 x 109/L, or ≥ 50 x 109/L if bone marrow infiltration or splenomegaly iii. ALT and AST level ≤3 x ULN iv. Direct bilirubin level ≤ 2 x ULN, unless due to Gilbert's syndrome v. CrCl ≥ 50mL/min (by Cockcroft-Gault formula) vi. PT, INR and aPTT ≤ 1.5 x ULN, unless receiving anticoagulation vii. LVEF within normal limits by MUGA or echocardiography
9. Able to provide written informed consent
10. Women of childbearing potential (or their partners) must use an effective form of contraception

Exclusion Criteria:

1. Current (or within 1 year) transformation to high grade lymphoma, including grade 3b follicular lymphoma (patients with historical high-grade transformation over 1 year ago are eligible)
2. Non-Fluorodeoxyglucose (FDG) avid disease
3. Prior allogenic stem cell transplantation (SCT) or solid organ transplant
4. Prior treatment with lenalidomide
5. Treatment with CAR-T therapy within 100 days of starting trial treatment
6. SCT or maintenance therapy planned within 24 weeks of starting treatment (patients planning SCT/maintenance after at least 24 weeks of treatment are eligible)
7. Immunochemotherapy with a platinum-containing regimen planned
8. Known serological positivity for HIV or uncontrolled HCV
9. Hepatitis B surface antigen (HBsAg) positive and/or detectable viral DNA. Patients positive for Hepatitis B core antibody (anti-HBc) but viral DNA negative are eligible
10. Other malignancy within 2 years of enrolment, excepting cervical carcinoma stage 1B or less, non-invasive basal cell or squamous cell skin carcinoma, non-invasive, superficial bladder cancer, prostate cancer with a current PSA level <0.1ng/mL, any curable cancer with a CR of > 2 years duration
11. Active systemic infection requiring treatment
12. Current or prior CNS involvement with lymphoma
13. History of allergy or anaphylaxis to anti-CD20 monoclonal antibody therapy
14. Known hypersensitivity to any of the experimental arm IMPs. Patients with a known hypersensitivity to a control arm regimen may still be eligible if they have no hypersensitivity to other potential control arm IMPs.
15. Serious medical or psychiatric illness likely to interfere with participation in this clinical study
16. Recent cancer treatment (chemotherapy, immunotherapy, biological therapy) within 4 weeks of starting trial treatment; systemic steroid treatment (prednisolone > 10mg daily (or equivalent)) within 7 days of cycle 1 day 1 dosing
17. Unwilling to use appropriate contraception methods whilst on study treatment and for 12 months following end of treatment (or 18 months for female patients whose ICT regimen contains obinutuzumab)
18. Women who are pregnant or breastfeeding
19. Prior treatment with the experimental therapy under investigation
20. Major surgery within 30 days of starting treatment
21. Severe arrhythmias, heart failure, previous myocardial infarction, acute inflammatory heart disease for ICT regimen containing doxorubicin, or severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease for ICT regimen containing rituximab