Table 1 Key patient eligibility criteria for the REFRACT trial

Inclusion Criteria

Biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma (biopsy within 6 months of trial entry)

Aged 18 years or over

Relapsed or refractory disease that in the opinion of the treating physician requires systemic therapy

Patient suitable for standard available therapy at the investigator’s discretion

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

Assessable fluorodeoxyglucose (FDG)-avid disease by PET-CT [15]

ECOG performance status of 0, 1 or 2

Adequate organ function defined as;

ANC ≥ 1.0 × 10⁹/L (growth factor use is permitted)

Platelet count ≥ 75 × 10⁹/L, or ≥ 50 × 10⁹/L if bone marrow infiltration or splenomegaly

ALT and AST level ≤ 3 x ULN

Direct bilirubin level ≤ 2 x ULN, unless due to Gilbert’s syndrome

CrCl ≥ 50mL/min (by Cockcroft-Gault formula)

PT, INR, and aPTT ≤ 1.5 x ULN, unless receiving anticoagulation

Able to provide written informed consent

Women of childbearing potential (or their partners) must use at least one effective form of contraception plus a barrier method of contraception during trial participation

Exclusion Criteria

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)

Non-FDG avid disease

Prior allogenic stem cell transplantation (SCT) or solid organ transplant

Prior treatment with lenalidomide within 12 months of starting trial treatment

Treatment with CAR-T therapy within 100 days of starting trial treatment

SCT or maintenance therapy planned within 24 weeks of starting treatment (patients planning SCT/maintenance after at least 24 weeks of treatment are eligible)

Immunochemotherapy with a platinum-containing regimen planned

Known serological positivity for HIV or uncontrolled HCV

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

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

Active systemic infection requiring treatment

Current or prior CNS involvement with lymphoma

History of allergy or anaphylaxis to anti-CD20 monoclonal antibody therapy

Known hypersensitivity to any of the novel 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.

Serious medical or psychiatric illness likely to interfere with participation in this clinical study

Recent cancer treatment (chemotherapy, immunotherapy, biological therapy) within 4 weeks of starting trial treatment; systemic steroid treatment (prednisolone > 10 mg daily (or equivalent)) within 7 days of cycle 1 day 1 dosing

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)

Women who are pregnant or breastfeeding

Prior treatment with a bispecific antibody

Major surgery within 30 days of starting treatment

Clinically significant cardiac disease including unstable angina within 6 months of study entry, acute MI within 6 months of study entry, New York Heart Association grade 3 or 4 congestive heart failure or known left ventricular ejection fraction < 45%)