REFRACT: Relapsed Follicular Lymphoma Randomised Trial Against Standard ChemoTherapy

Sponsor

University of Birmingham (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05848765

Collaborator

Cancer Research UK (Other), Genmab (Industry)

284

Enrollment

Locations

Arms

102

Anticipated Duration (Months)

11.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Follicular Lymphoma Refractory Follicular Lymphoma	Drug: Epcoritamab Drug: Lenalidomide Drug: Rituximab Drug: Obinutuzumab Drug: Bendamustine Drug: Vincristine Drug: Doxorubicin Drug: Cyclophosphamide Drug: Prednisone Drug: Investigation agent 2 Drug: Investigation agent 3	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

284 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

May 31, 2023

Anticipated Primary Completion Date :

May 31, 2029

Anticipated Study Completion Date :

Nov 30, 2031

Arms and Interventions

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: 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

Outcome Measures

Primary Outcome Measures

Complete metabolic response (CMR) [24 weeks]
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

Secondary Outcome Measures

Overall metabolic response [24 weeks]
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
Progression free survival (PFS) [10 years]
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
Overall survival (OS) [10 years]
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
Duration of response (DoR) [10 years]
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
Duration of complete response (DoCR) [10 years]
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
Time to next treatment (TTNT) [10 years]
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
Adverse events (AEs) [Collected from start of treatment until 60 days after treatment]
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
Quality of Life (QoL) [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)]
Measured using the EQ-5D-5L and FACT-Lym
Quality of Life (QoL) [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)]
Measured using the FACT-Lym

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	NHS Grampian	Aberdeen	United Kingdom
2	Belfast Health & Social Care Trust	Belfast	United Kingdom
3	University Hospitals Birmingham NHS Foundation Trust	Birmingham	United Kingdom
4	Blackpool Teaching Hospitals NHS Foundation Trust	Blackpool	United Kingdom
5	Cambridge University Hospitals NHS Foundation Trust	Cambridge	United Kingdom
6	Cardiff and vale University LHB	Cardiff	United Kingdom
7	University Hospitals Coventry and Warwickshire NHS Trust	Coventry	United Kingdom
8	Croydon Health Services NHS Trust	Croydon	United Kingdom
9	NHS Greater Glasgow and Clyde	Glasgow	United Kingdom
10	The Leeds Teaching Hospitals NHS Trust	Leeds	United Kingdom
11	The Clatterbridge Cancer Centre NHS Foundation Trust	Liverpool	United Kingdom
12	Guy's and St Thomas' NHS Foundation Trust	London	United Kingdom
13	King's College Hospital NHS Foundation Trust	London	United Kingdom
14	The Royal Marsden NHS Foundation Trust	London	United Kingdom
15	University College London Hospital NHS Foundation Trust	London	United Kingdom
16	The Christie NHS Foundation Trust	Manchester	United Kingdom
17	The Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle	United Kingdom
18	Norfolk and Norwich University Hospitals NHS Foundation Trust	Norwich	United Kingdom
19	Nottingham University Hospitals NHS Trust	Nottingham	United Kingdom
20	Oxford University Hospitals NHS Foundation Trust	Oxford	United Kingdom
21	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield	United Kingdom
22	University Hospital Southampton NHS Foundation Trust	Southampton	United Kingdom
23	University Hospital of North Midlands NHS Trust	Stoke-on-Trent	United Kingdom
24	Swansea Bay University Local Health Board	Swansea	United Kingdom
25	Torbay and South Devon NHS Foundation Trust	Torquay	United Kingdom