Chronic lymphocytic leukaemia (CLL) Cancer
Conditions
Interventions
Current interventions as of 07/07/2025:
In the randomisation pathway, participants will be randomised 1:1 to either intermittent treatment with a BTK inhibitor, known as the ‘pausing treatment’ arm, o
Sponsors
University of Leeds
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current key inclusion criteria as of 25/09/2025: Trial Registration Inclusion Criteria: 1. At least 18 years old 2. A diagnosis of chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) (by 2018 iwCLL criteria) 3. World Health Organisation (WHO) performance status (PS) of 0,1, or 2 4. Biochemical values must be within the following limits within 4 weeks prior to randomisation/or registration for the Clinical Need Cohort and at baseline: 4.1. Alanine aminotransferase (ALT) =3 x upper limit of normal (ULN) OR Aspartate aminotransferase (AST) =3 x ULN. 4.2. Total bilirubin =1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin 5. Agree to follow the pregnancy prevention plan* 6. Able to provide informed consent *Participants randomised to the pause/resume arm must adhere to this whilst receiving treatment with a BTK inhibitor, but will not be required to follow contraceptive measures during the planned treatment breaks Additional inclusion criteria for participants in the Clinical Need Cohort: 1. Meet all of the Registration Inclusion criteria 2. Currently receiving ibrutinib and nearing the end of or having completed 6 years of ibrutinib treatment on FLAIR or IcICLLe** 3. Have signs of progressive or returning CLL after completing 6 years of ibrutinib treatment within FLAIR or IcICLLe, but prior to entry into STATIC Additional inclusion criteria for Front Line participants entering the randomisation trial: 1. Meet all of the Registration Inclusion criteria 2. Currently receiving front-line treatment with ibrutinib and received at least 6 years through standard care, or currently receiving front-line treatment with ibrutinib and approaching the end of 6 years of treatment in FLAIR or IcICLLe, or having already completed 6 years of ibrutinib treatment in FLAIR or IcICLLe. ** 3. In clinical remission, all of the following: 3.1. No palpable lymph nodes; 3.2. No palpable spleen; and 3.3. Lymphocyte count below 5x10^9/L continuously for at least 12 months before randomisation **Patients should enter STATIC on completion of treatment in FLAIR or IcICLLe, with no break in therapy, with the exception of participants who have completed the 6 years of treatment in FLAIR or IcICLLe prior to STATIC opening Additional inclusion criteria for Previously Treated participants entering the randomisation trial: 1. Meet all of the registration inclusion criteria 2. Currently receiving ibrutinib or acalabrutinib for at least the previous 36 months as the second or subsequent line of treatment. There is no restriction on the maximum duration of treatment prior to enrolment. 3. In clinical remission, fulfilling all of the following: 3.1. No palpable lymph nodes; 3.2. No palpable spleen; and 3.3. Lymphocyte count below 5x10^9/L at the time of assessing eligibility Previous inclusion criteria as of 07/07/2025: Trial Registration Inclusion Criteria: 1. At least 18 years old 2. A diagnosis of chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) (by 2018 iwCLL criteria) 3. World Health Organisation (WHO) performance status (PS) of 0,1 or 2 4. Biochemical values must be within the following limits within 4 weeks prior to randomisation/or registration for the Clinical Need Cohort and at baseline: 4.1. Alanine aminotransferase (ALT) =3 x upper limit of normal (ULN) OR Aspartate aminotransferase (AST) =3 x ULN. 4.2. Total bilirubin =1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 07/07/2025: Trial Registration Exclusion Criteria: 1. Pregnant females 2. Known intolerance or hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. 3. Receipt of live vaccination within 4 weeks prior to registration and for the duration of the study. 4. History or current evidence of Richter’s transformation 5. Major surgery within 4 weeks prior to randomisation/or registration for the Clinical Need Cohort 6. Active infection 7. Concomitant warfarin (or equivalent vitamin K inhibitor) 8. Central nervous system involvement with CLL 9. Cardiac failure; including symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded) 10. Respiratory impairment (e.g. bronchiectasis or severe COPD) 11. Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study 12. Positive serology for Hepatitis B (HB), defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status),aHB DNA test will be performed and if positive, the patients will be excluded. During treatment, these participants should be monitored and managed to prevent HBV reactivation. 13. Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a test for hepatitis C RNA (for example, HCV RNA PCR). If positive, the patients will be excluded. 14. Persisting severe pancytopenia (neutrophils 20mg/day 16. Uncontrolled Active haemolysis 17. History of stroke or intracranial haemorrhage within 6 months prior to enrolment. 18. Requirement for treatment with a strong CYP3A inhibitor or inducer 19. New treatment with two or more antiplatelet drugs, treatment that has been administered at a stable dose for at least 3 months prior to registration is permissible Additional exclusion criteria for participants in the Clinical Need Cohort: 1. Meet none of the registration exclusion criteria 2. Active Disease, as per the 2018 iwCLL criteria requiring an alternative therapy. 3. Received treatment other than ibrutinib for CLL since completing FLAIR 4. Be eligible for front-line randomisation 5. Ibrutinib treatment break for toxicity/patient choice for more than 28 days in the last 12 months (added 07/11/2024) Additional exclusion criteria for Front-Line participants entering the randomisation trial: 1. Meet any of the registration exclusion criteria 2. Disease progression (according to 2018 iwCLL criteria) 3. Ibrutinib treatment break for toxicity/patient choice for more than 28 days in the last 12 months Additional exclusion criteria for Previously Treated participants entering the randomisation trial: 1. Meet any of the registration exclusion criteria 2. Disease progression (according to 2018 iwCLL criteria) 3. Ibrutinib or acalabrutinib treatment break for toxicity/patient choice for more than 28 days in the last 12 months 4. Any illness, disease or condition, such as active cancer or secondary primary malignancy (SPM), with a prognosis of less than 5 years 5. Patients with a creatinine clearance of less than 30ml/min (
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time to treatment strategy failure. Time to treatment strategy failure is defined as the time from randomisation to time of treatment strategy failure. Treatment strategy failure is defined as the first documented instance of active disease that does not respond to treatment, or death from any cause measured using patient records throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Overall survival will be measured for the randomisation trial as the time from randomisation to the time of death from any cause. In the clinical need cohort this will be calculated as the time from registration to the time of death from any cause. 2. Toxicity and tolerability based on adverse events, as graded by CTCAE V5.0 and determined by routine clinical assessments at each centre. 3. Cost-effectiveness is defined as a cost per incremental QALY below £20,000 and/or a positive incremental net monetary benefit. The cost-effectiveness of treatment options will be evaluated with respect to this criteria. 4. Quality of life will be assessed using the patient-reported outcome measures: EORTC-QLQ-C30, EORTC-QLQ-CLL and EQ-5D-5L. This will be measured in the randomisation trial only and will be recorded at baseline and after 3, 6 12, 18, 24, 30, 36 and 48 months of trial treatment. 5. Summative treatment-free Interval is defined as the time to treatment strategy failure, excluding any time spent on treatment. 6. Response to retreatment in intermittent treatment arm will be assessed as a patients response (partial remission (PR), stable disease (SD) or progressive disease (PD) according to the response criteria defined by the standard 2018 iwCLL criteria) between 9 and 12 months after restarting treatment. 7. Time to next treatment is defined as the time from randomisation to the start date of the next line of treatment. For the Clinical Need Cohort, this will be time from registration to the start date of the next line of treatment. 8. Response to next treatment for CLL will be assessed as the best response (PR, SD or PD according to the response criteria defined by the standard 2018 iwCLL criteria) achieved by a participant at any timepoint. 9. Rate of resistance mutation between trial arms will be assessed as the proportion of participants in each arm with a detectable BTK mutation at baseline, 24 months and 48 months for all randomised participants, and at | — |
Countries
England, Scotland, United Kingdom, Wales
Outcome results
None listed