Chronic lymphocytic leukaemia Cancer Chronic lymphocytic leukaemia of B-cell type
Conditions
Interventions
Current intervention as of 13/11/2023:
All arms are now closed to recruitment.
Participants were randomised on a 1:1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and ritux
Sponsors
University of Leeds (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 13/11/2023: For standard-risk pathway: 1. At least 18 years old. Maximum age of 75 years old. 2. B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma 3. Binet's Stages C, B or Progressive Stage A 4. Requiring therapy by the IWCLL criteria in that they must have at least one of the following: 4.1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia. 4.2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 4.3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy 4.4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30 x 10^9/L 4.5. A minimum of any one of the following disease-related symptoms must be present: 4.5.1. Unintentional weight loss more than or equal to 10% within the previous 6 months. 4.5.2. Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities) 4.5.3. Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection 4.5.4. Night sweats for more than 1 month without evidence of infection 5. Considered fit for treatment with FCR as determined by the treating clinician 6. World Health Organisation (WHO) performance status (PS) of 0, 1 or 2 7. Able to provide written informed consent 8. Biochemical values must be within the following limits within 14 days prior to randomization and at baseline: 8.1. Alanine aminotransferase (ALT) 3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) 3 x ULN. 8.2. Total bilirubin = 1.5 x ULN, unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin For the genetically high-risk pathway 1. TP53 abnormality confirmed by central laboratory 2. At least 18 years old (no upper limit) 3. Meeting all the inclusion criteria for the standard risk pathway stated, with the exception of ‘considered fit for treatment with FCR as determined by the treating clinician’ _____ Previous inclusion criteria: 1. At least 18 years old. Maximum age of 75 years old. 2. B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma 3. Binet?s Stages C, B or Progressive Stage A 4. Requiring therapy by the IWCLL criteria in that they must have at least one of the following: 4.1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia. 4.2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 4.3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy 4.4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30 x 10^9/L 4.5. A minimum of any one of the following disease-related symptoms must be present: 4.5.1. Unintentional weight loss more than or equal to 10% within the previous 6 months. 4.5.2. Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities) 4.5.3. Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection 4.5.4. Night sweats for more than 1 month without evidence of infe
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 07/09/2018: 1. Prior therapy for CLL 2. History or current evidence of Richter's transformation 3. Major surgery within 4 weeks prior to randomisation 4. Active infection 5. Above 20% P53 deletion, determined by FISH 6. Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies 7. Concomitant warfarin or equivalent vitamin K inhibitor - added 29/06/2017: or other oral anticoagulant treatment; anyone requiring anticoagulation treatment for greater than 6 months is not eligible for trial entry 8. Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction 9. Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile 10. CNS involvement with CLL 11. 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) 12. Respiratory impairment (bronchiectasis or moderate COPD) 13. Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study 14. Inability to swallow oral medication 15. Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc) 16. Known HIV positive 17. 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), a HB DNA test will be performed and if positive the subject will be excluded 18. Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result 19. History of prior malignancy, with the exception of the following: 19.1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician 19.2. Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease 19.3. Adequately treated cervical carcinoma in situ without current evidence of disease 20. Persisting severe pancytopenia (neutrophils 10 mg/day 22. Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10 mg or less per day can be entered into the trial) 23. Patients with a creatinine clearance of less than 30 ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula) 24. History of stroke or intracranial hemorrhage wi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Current primary outcome measure as of 07/09/2018: 1. Whether I+V is superior to FCR in terms of progression-free survival. 2. Whether I+V is superior to I in terms of Minimal Residual Disease negativity. The proportion of concurrently randomised participants who are MRD negative in the bone marrow at any time during the trial will be summarised by treatment arm and compared using a binary logistic regression model adjusted for the minimisation factors and trial stage, excluding centre, and Kaplan-Meier curves will be presented. The analysis of MRD negativity will be initially carried out at 2 years after the close of recruitment. Previous primary outcome measure: The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of progression-free survival, and whether IR toxicity rates are favourable. | — |
Secondary
| Measure | Time frame |
|---|---|
| Current secondary outcome measures as of 10/09/2018: 1. PFS of I+V in comparison with I. This is assessed using time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression-free. 2. PFS of I in comparison with FCR. This is assessed using time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression free. 3. Overall survival. This is assessed using time from randomisation to date of death from any cause. Participants not known to have died will be censored at the date they were last known to be alive. 4. Proportion of participants obtaining undetectable MRD, as defined by IWCLL criteria. A negative MRD is defined as the presence of <0.01% CLL cells in the bone marrow. Achievement of MRD negativity is defined as a MRD negative results at any time over the length of the trial. 5. Stopping I-containing therapy in MRD negative patients. Participants receiving I, IR or I+V who achieve MRD negativity in the bone marrow will be able to stop treatment. MRD levels will be monitored over time following stopping treatment. 6. Restarting I-containing therapy on MRD relapse. Those who relapse at the MRD level will restart treatment and will be assessed further for MRD response. 7. Response to therapy, as defined by IWCLL criteria. For participants randomised to FCR or IR, response is assessed at 3 months post-treatment with FCR or R and again at the end of treatment with ibrutinib for participants randomised to IR. For participants randomised to I or I+V, response is assessed at 9 months post-randomisation and again at the end of treatment. 8. Safety and toxicity assessed using adverse events reported throughout the trial, | — |
Countries
England, Northern Ireland, Scotland, United Kingdom, Wales
Contacts
Public ContactSue Bell
Outcome results
None listed