RadiothErapy priMIng for CAR-T

Study Overview
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Brief Summary
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The REMIT trial will investigate radiotherapy as a preferred bridging method prior to Tisagenlecleucel infusion in patients with relapsed or refractory Diffuse Large B Cell Lymphoma

Detailed Description
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The REMIT Trial is an open label, single arm phase IIa study investigating Radiotherapy as preferred bridging method prior to Tisagenlecleucel treatment in patients with relapsed or refractory Diffuse Large B Cell Lymphoma approved to receive CD19 CAR-T cells as per their licensed indication. The trial will recruit 20 patients who have been approved to receive Tisagenlecleucel treatment and where the tumour is amendable to radiotherapy as per standard of care. Trial subjects (patients) during a 14 day screening phase will have their metabolic tumour burden assessed by PET-CT and bridging radiotherapy will be planned. Bridging radiotherapy will commence immediately after leukapheresis with dose adjustments according to disease burden and localisation. Disease areas requiring effective long-term control will receive full dose radiotherapy, 20 - 30Gy /5-15# and other areas will receive low dose radiotherapy, 4Gy / 2# for optimal tumour debulking and priming effects. Standard lymphodepletion will be given day -5 to day -3 followed by Tisagenlecleucel infusion on day 0. A window of 14-21 days will be left from last dose of radiotherapy and day 0. Patients will be followed up at 3 and 6 months after Tisagenlecleucel infusion for a minimum of 12 months.

Official Title
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RadiothErapy priMIng for CAR-T

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Radiation: Bridging Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥ 18 years Histologically proven DLBCL, including transformed follicular or marginal zone lymphoma Measurable disease on cross-sectional imaging that is at least 1.5cm in the longest diameter and measurable in two perpendicular dimensions Relapsed/refractory after 2 or more standard immuno-chemotherapies Approved to receive Tisagenlecleucel as per the licenced indication Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Disease accessible for repeat biopsies (Selected patients only) Disease amenable to radiotherapy as assessed by the treating clinical oncologist Willing and able to comply with the requirements of the protocol, including contraceptive advice as per the protocol Exclusion Criteria: Prior radiotherapy at location/dose that would interfere with application of radiotherapy or outcome measures in this trial Women who are pregnant or breast feeding Previous therapy with any genetically modified autologous or allogeneic T-cell immunotherapy, unless treated with doses of genetically modified autologous or allogeneic T-cell immunotherapy within an abandoned dosing cohort in a first in human dose-escalation phase I clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bridging Radiotherapy<br>Disease areas requiring effective long-term control will receive full-dose radiotherapy (20-30Gy/5-15#); other areas will receive low dose (4Gy/2#) | Radiation: Bridging Radiotherapy<br>* Bridging Radiotherapy will start immediately after leukapheresis and before Tisagenlecleucel treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients starting lymphodepletion on the planned start date without delay | To evaluate whether there is any delay in patients starting lymphodepletion | From planned start date of lymphodepletion until actual start date of lymphodepletion, assessed up to 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best overall response after Tisagenlecleucel infusion as per International Working Group 2014 criteria | Proportion of patients achieving a Complete Response (CR) or Partial Response (PR) | After Tisagenlecleucel infusion through to study completion, an average of 24 months | 
| Overall response rate at 3 months and 6 months after Tisagenlecleucel infusion | Overall response rate after Tisagenlecleucel infusion | At 3 and 6 months after Tisagenlecleucel infusion | 
| Complete metabolic response at 3 months and 6 months after Tisagenlecleucel infusion | Complete metabolic response after Tisagenlecleucel infusion | At 3 and 6 months after Tisagenlecleucel infusion | 
| Duration of response | Time from date of first response confirmation to the first date of progressive disease confirmation | From initial response until the date of first documented disease progression, assessed up to 24 months | 
| Median progression free survival and progression free survival at 12 months | Progression Free Survival after Tisagenlecleucel infusion | 12 months after Tisagenlecleucel infusion | 
| Median event-free survival and event-free survival at 12 months | Event-free survival after Tisagenlecleucel infusion | 12 months after Tisagenlecleucel infusion | 
| Median overall survival and overall survival at 12 months | Overall Survival after Tisagenlecleucel infusion | 12 months after Tisagenlecleucel infusion | 
| Treatment emergent adverse events | Adverse events being reported during and after treatment | From start of Tisagenlecleucel infusion until 30 days post Tisagenlecleucel infusion | 
| Incidence of grade 3 or higher cytokine release syndrome and immune effector cell associated neurotoxicity syndrome | Percentage of grade 3 or higher cytokine relapse syndrome and immune effector cell associated neurotoxicity syndrome events | From start of Tisagenlecleucel infusion through to study completion, an average of 24 months | 
| Neutrophil levels at 1, 3, 6 months after Tisagenlecleucel infusion | Neutrophil counts to be reported after Tisagenlecleucel infusion | At 1, 3 and 6 months after Tisagenlecleucel infusion | 
| Platelet levels at 1, 3, 6 months after Tisagenlecleucel infusion | Platelet counts to be reported after Tisagenlecleucel infusion | At 1, 3 and 6 months after Tisagenlecleucel infusion |