Relapsed Follicular Lymphoma Randomised Trial Against Standard ChemoTherapy

Official title

Relapsed Follicular Lymphoma Randomised Trial Against Standard ChemoTherapy (REFRACT): A Randomised Phase II Trial of Investigator Choice Standard Therapy Versus Sequential Novel Therapy Experimental Arms

Overview

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.

Detailed description

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).

Interventions

• Drug Epcoritamab
  Bispecific antibody
• Drug Lenalidomide
  Immunomodulatory agent
• Drug Rituximab
  Monoclonal antibody
• Drug Obinutuzumab
  Monoclonal antibody
• Drug Bendamustine
  Alkylating agent (chemotherapy drug)
• Drug Vincristine
  Antineoplastic, Vinca Alkaloid
• Drug Doxorubicin
  Anthracycline
• Drug Cyclophosphamide
  Alkylating agent (chemotherapy drug)
• Drug Prednisone
  Corticosteroid
• Drug Investigation agent 2
  The drug used in round 2 is yet to be confirmed, round 2 is estimated to open in Q4 2025 and the record will be updated when the drug has been confirmed

Primary outcome measures

• Complete metabolic response (CMR) [Time frame: 24 weeks]

Secondary outcome measures (9)

• Overall metabolic response [Time frame: 24 weeks]
• Progression free survival (PFS) [Time frame: 10 years]
• Overall survival (OS) [Time frame: 10 years]
• Duration of response (DoR) [Time frame: 10 years]
• Duration of complete response (DoCR) [Time frame: 10 years]
• Time to next treatment (TTNT) [Time frame: 10 years]
• Adverse events (AEs) [Time frame: Collected from start of treatment until 60 days after treatment]
• Quality of Life (QoL) [Time frame: Collected pre-treatment, day 1 of cycle 3 (28 day cycles), 24 weeks from treatment start and then every 24 weeks in non-progressed patients until the end of the study (10 years)]
• Quality of Life (QoL) [Time frame: Collected pre-treatment, day 1 of cycle 3 (28 day cycles), 24 weeks from treatment start and then every 24 weeks in non-progressed patients until the end of the study (10 years)]

Eligibility criteria

Inclusion criteria

• Biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma (biopsy within 3 months of trial entry)
• Aged 18 years or over
• Advanced disease that in the opinion of the treating physician requires treatment
• 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 disease by PET-CT (at least one involved node with long diameter >1.5cm, or extranodal lesion >1cm )
• ECOG performance status of 0, 1 or 2 at trial entry
• 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
• Able to provide written informed consent
• Women of childbearing potential (or their partners) must use an effective form of contraception

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-Fluorodeoxyglucose (FDG) avid disease
• Prior allogenic stem cell transplantation (SCT) or solid organ transplant
• Prior treatment with lenalidomide
• 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 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.
• 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 > 10mg 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 the experimental therapy under investigation
• Major surgery within 30 days of starting treatment
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 25 centers

• NHS Grampian — Aberdeen
• Belfast Health & Social Care Trust — Belfast
• University Hospitals Birmingham NHS Foundation Trust — Birmingham
• Blackpool Teaching Hospitals NHS Foundation Trust — Blackpool
• Cambridge University Hospitals NHS Foundation Trust — Cambridge
• Cardiff and vale University LHB — Cardiff
• University Hospitals Coventry and Warwickshire NHS Trust — Coventry
• Croydon Health Services NHS Trust — Croydon
• … and 17 more centers

Publications

• Gaskell C, Linton K, Bishton M, McIlroy G, Lax S, Fox S, Hopkins L, Collings R, Rhodes M, Seale T, Jackson A. The REFRACT trial: implementation of Bayesian power priors in a randomised, sequential phase II adaptive platform trial. BMC Med Res Methodol. 2025 May 3;25(1):121. doi: 10.1186/s12874-025-02575-5. PMID 40319227
• McIlroy G, Lax S, Gaskell C, Jackson A, Rhodes M, Seale T, Fox S, Hopkins L, Okosun J, Barrington SF, Ringshausen I, Ramsay AG, Calaminici M, Linton K, Bishton M. Investigator choice of standard therapy versus sequential novel therapy arms in the treatment of relapsed follicular lymphoma (REFRACT): study protocol for a multi-centre, open-label, randomised, phase II platform trial. BMC Cancer. 2024 PMID 38528445

Identifiers

NCT: NCT05848765 · RG_22-020

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗