Relapsed Follicular Lymphoma Randomised Trial Against Standard ChemoTherapy (REFRACT)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Relapsed Follicular Lymphoma; Refractory Follicular Lymphoma
• Intervention / Treatment: Drug: Doxorubicin; Drug: Prednisone; Drug: Epcoritamab; Drug: Lenalidomide; Drug: Investigation agent 2; Drug: Investigation agent 3; Drug: Rituximab; Drug: Obinutuzumab; Drug: Bendamustine; Drug: Vincristine; Drug: Cyclophosphamide

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).

• Study Type: Interventional
• Enrollment (Estimated): 284
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Trial Coordinator; Phone Number: 0121 371 7861; Email: refract@trials.bham.ac.uk

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom
    • Not yet recruiting
    • NHS Grampian
  • Belfast, United Kingdom
    • Not yet recruiting
    • Belfast Health & Social Care Trust
  • Birmingham, United Kingdom
    • Not yet recruiting
    • University Hospitals Birmingham NHS Foundation Trust
  • Blackpool, United Kingdom
    • Not yet recruiting
    • Blackpool Teaching Hospitals NHS Foundation Trust
  • Cambridge, United Kingdom
    • Not yet recruiting
    • Cambridge University Hospitals NHS Foundation Trust
  • Cardiff, United Kingdom
    • Not yet recruiting
    • Cardiff and vale University LHB
  • Coventry, United Kingdom
    • Not yet recruiting
    • University Hospitals Coventry and Warwickshire NHS Trust
  • Croydon, United Kingdom
    • Not yet recruiting
    • Croydon Health Services NHS Trust
  • Glasgow, United Kingdom
    • Not yet recruiting
    • NHS Greater Glasgow and Clyde
  • Leeds, United Kingdom
    • Not yet recruiting
    • The Leeds Teaching Hospitals NHS Trust
  • Liverpool, United Kingdom
    • Not yet recruiting
    • The Clatterbridge Cancer Centre NHS Foundation Trust
  • London, United Kingdom
    • Not yet recruiting
    • Guy's and St Thomas' NHS Foundation Trust
  • London, United Kingdom
    • Not yet recruiting
    • The Royal Marsden NHS Foundation Trust
  • London, United Kingdom
    • Not yet recruiting
    • King's College Hospital NHS Foundation Trust
  • London, United Kingdom
    • Not yet recruiting
    • University College London Hospital NHS Foundation Trust
  • Manchester, United Kingdom
    • Recruiting
    • The Christie NHS Foundation Trust
  • Newcastle, United Kingdom
    • Not yet recruiting
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
  • Norwich, United Kingdom
    • Not yet recruiting
    • Norfolk and Norwich University Hospitals NHS Foundation Trust
  • Nottingham, United Kingdom
    • Recruiting
    • Nottingham University Hospitals NHS Trust
  • Oxford, United Kingdom
    • Not yet recruiting
    • Oxford University Hospitals NHS Foundation Trust
  • Sheffield, United Kingdom
    • Not yet recruiting
    • Sheffield Teaching Hospitals NHS Foundation Trust
  • Southampton, United Kingdom
    • Not yet recruiting
    • University Hospital Southampton NHS Foundation Trust
  • Stoke-on-Trent, United Kingdom
    • Not yet recruiting
    • University Hospital of North Midlands NHS Trust
  • Swansea, United Kingdom
    • Not yet recruiting
    • Swansea Bay University Local Health Board
  • Torquay, United Kingdom
    • Not yet recruiting
    • Torbay and South Devon Nhs Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Round 1: Epcoritamab and lenalidomide; Epcoritamab (weekly for cycles 1 and 2 and on day 1 of cycles 3-12 for up to 12 cycles) and lenalidomide (daily for days 1-21 of each cycle for up for 12 cycles), cycles will be 28 day cycles.	Drug: Epcoritamab; Bispecific antibody; Drug: Lenalidomide; Immunomodulatory agent
Experimental: Round 2; Investigation agent 2	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
Experimental: Round 3; Investigation agent 3	Drug: Investigation agent 3; The drug used in round 3 is yet to be confirmed, round 3 is estimated to open in Q3 2027 and the record will be updated when the drug has been confirmed
Active Comparator: All rounds: Investigator Choice Therapy; Choice of therapy to be selected by the Investigator for each patient prior to randomisation. The Investigator will choose between; RCHOP, RCVP, rituximab and bendamustine, rituximab and lenalidomide or bendamustine and obinutuzumab.	Drug: Doxorubicin; Anthracycline; Drug: Prednisone; Corticosteroid; Drug: Lenalidomide; Immunomodulatory agent; Drug: Rituximab; Monoclonal antibody; Drug: Obinutuzumab; Monoclonal antibody; Drug: Bendamustine; Alkylating agent (chemotherapy drug); Drug: Vincristine; Antineoplastic, Vinca Alkaloid; Drug: Cyclophosphamide; Alkylating agent (chemotherapy drug)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete metabolic response (CMR)	CMR will be assessed by PET-CT using the Deauville 5-point scale and Lugano 2014 criteria. Patients who die from any cause or relapse/progress prior to this time-point will be considered non-responders. Patients who don't have a PET-CT scan within the protocol defined window or withdraw from the trial prior to this time-point will be considered non outcome evaluable. Patients who undergo stem-cell transplant (SCT) within 24 weeks of randomisation, patients who fail to start treatment and patients whose ineligibility is deemed to impact upon response to treatment will be replaced and hence not included in the analysis of this outcome	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall metabolic response	Complete metabolic response (CMR) and partial metabolic response (PMR) will be assessed by PET-CT. Patients who die from any cause or relapse/progress prior to this time-point will be considered non-responders. Patients who undergo stem-cell transplant (SCT) within 24 weeks of randomisation, patients who fail to start treatment and patients whose ineligibility is deemed to impact upon response to treatment will be replaced and hence not included in the analysis of this outcome	24 weeks
Progression free survival (PFS)	The time from randomisation to the date of first disease progression or death. Patients who are alive and relapse/progression at the time of analysis will be censored at their date last seen	10 years
Overall survival (OS)	The time from randomisation to the date of death from any cause. Patients who are alive at the time of analysis will be censored at their date last seen	10 years
Duration of response (DoR)	The time from complete and partial metabolic response by PET-CT to relapse/progression or death from any cause. Patients who are alive and relapse/progression free at the time of analysis will be censored at their date last seen	10 years
Duration of complete response (DoCR)	The time from complete metabolic response by PET-CT to relapse/progression or death from any cause. Patients who are alive and relapse/progression free at the time of analysis will be censored at their date last seen	10 years
Time to next treatment (TTNT)	The time from randomisation to the start date of next treatment for lymphoma. Patients who are responding (CMR or PMR) who receive consolidation radiotherapy will not be considered an event and will be censored at their date last seen if no other treatment for lymphoma is reported. Patients who die without having started next lymphoma treatment will be considered a competing risk at their date of death, and patients who are alive and have not started next lymphoma treatment at the time of analysis will be censored at their date last seen	10 years
Adverse events (AEs)	Collected and reported in accordance with CTCAE version 5 defined as the number of patients who experience one or more grade 3 or 4 adverse events or serious adverse events of any grade	Collected from start of treatment until 60 days after treatment
Quality of Life (QoL)	Measured using the EQ-5D-5L and FACT-Lym	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)	Measured using the FACT-Lym	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)

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: Cancer Research UK; Genmab

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2023
• Primary Completion (Estimated): May 31, 2029
• Study Completion (Estimated): November 30, 2031

Study Registration Dates

• First Submitted: April 18, 2023
• First Submitted That Met QC Criteria: April 28, 2023
• First Posted (Actual): May 8, 2023

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Lymphoma; Epcoritamab
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Follicular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Lenalidomide; Bendamustine Hydrochloride; Rituximab; Prednisone; Doxorubicin; Vincristine; Obinutuzumab
• Other Study ID Numbers: RG_22-020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No