Title: A Randomised Phase III Trial Comparing Intermittent with Continuous Treatment Strategies in chronic lymphocytic leukaemia (CLL)
Funder: Department of Health and Social Care

Abstract: Chronic lymphocytic leukaemia (CLL) is a cancer that affects the blood and bone marrow. It tends to progress slowly, and is incurable. CLL is the most common leukaemia in adults. The first treatment for CLL is chemotherapy. This is usually given for around 6 months, and often controls the CLL for several years. Ibrutinib is a new targeted treatment which is used for patients who relapse after their chemotherapy. It is also being tested (in a randomised trial called FLAIR) as an alternative to chemotherapy for the first treatment of CLL. Ibrutinib works by blocking signals within cancer cells that make them grow and divide. Unlike chemotherapy, patients continue taking ibrutinib even when their CLL is well controlled and stable_x000D_ _x000D_ Ibrutinib is taken as 3 tablets once a day. The most common side effects that happen for about 1 in 5 patients include sickness, diarrhoea, muscle and bone pain, and low blood counts. Other side effects include an increased risk of bleeding and infection and, if treatment continues for a long time, heart problems. Patients whose CLL has relapsed will take ibrutinib for an average of 4 years, and those on their first treatment will take ibrutinib for an average of 10 years. Ibrutinib is expensive, and four years treatment costs the NHS £295,000 per person_x000D_ _x000D_ At the moment ibrutinib treatment is continued until either it stops working, or the side effects become so bad that it has to be stopped. Research has suggested that stopping treatment when we are sure the CLL is controlled and restarting it if the CLL progresses again may be as good as continuous treatment, and it is possible it may be better for controlling CLL. Having periods when patients can stop treatment would reduce side effects, which we think would improve their quality of life. Also, this would reduce the financial cost to the NHS_x000D_ _x000D_ This proposal aims to find this out whether stopping and restarting ibrutinib treatment is as good as continuous treatment for CLL. Our trial will recruit 800 patients at 100 UK hospitals who have been taking ibrutinib for at least two years and have stable, low levels of CLL. Patients will either have their ibrutinib stopped and restarted when needed, or they will have the usual care of continuous treatment. Which treatment each patient gets will be decided at random by a computer. All patients will be in the trial for at least 3 years and they will be monitored closely every 3 months. For those who have had treatment stopped, treatment will be restarted when the level of CLL rises again. Once the CLL is controlled, treatment will stop again. For all patients in the trial, ibrutinib will be stopped when the CLL level is high, as this means ibrutinib is no longer working and it is time to try another treatment. This is called ‘disease progression’_x000D_ _x000D_ We want to know whether disease progression happens at about the same time for patients who have ibrutinib treatment stopped and restarted, as for those who have continuous treatment. We are also interested in side effects, quality of life, financial costs for the NHS, how long patients have off treatment, and how long they survive_x000D_ _x000D_ We have talked with patients and patient representatives who agree this is important research for people with CLL. Patients and patient representatives will be involved at all stages of the study, including preparing summaries of the research findings for patient organisations, websites, the press, and for people who took part in the study

Lay abstract: Design_x000D_ A prospective, multicentre, open-label, randomised, controlled, 2-arm, parallel-group, non-inferiority study to comparing an intermittent treatment strategy (experimental arm) with continuous treatment (control arm) with ibrutinib (or other BTK inhibitor) for patients with CLL who have responded well to treatment with the BTK inhibitor. Participants will be randomised on a 1:1 basis to an intermittent treatment strategy or continuous treatment._x000D_ _x000D_ Setting_x000D_ 100 NHS cancer centres experienced in diagnosis and management of CLL._x000D_ _x000D_ Health technology being assessed_x000D_ An intermittent treatment strategy of ibrutinib (or other BTK inhibitor) will be compared with continuous treatment. Participants randomised to intermittent treatment will cease treatment immediately following randomisation, and restart when the restart criteria are met. When treatment restarts, participants restart treatment with the same BTK inhibitor as they received initially at the standard dose until the treatment stop criteria are met. The stopping and starting criteria are assessed locally every 3 months at standard clinic visits. Participants can stop and restart treatment multiple times until either the treatment strategy fails, they withdraw from the strategy, or the trial ends._x000D_ _x000D_ Measurement of costs and outcomes_x000D_ Primary: time to strategy failure_x000D_ Secondary: overall survival, toxicity and tolerability, cost effectiveness, quality of life, length of time off treatment in the intermittent treatment arm, time to next treatment for CLL and response to next treatment for CLL._x000D_ _x000D_ Sample size_x000D_ 800 patients will be randomised over a 6 year period. We expect to be able to recruit 45% of patients from our front-line CLL trial FLAIR and 55% from relapsed/refractory patients._x000D_ _x000D_ Project timeline_x000D_ Set up: 1-12 months_x000D_ Recruitment: 13-84 months, including recruitment feasibility assessment months 18-30 and interim analysis months 73-75_x000D_ Follow up: 85-120 months_x000D_ Analysis: 121-123 months_x000D_ Long term survival: month 195

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS