Front-line therapy in CLL: assessment of ibrutinib-containing regimes

INTERVENTION: Current interventions as of 07/09/2018: Participants will be randomised on a 1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR), ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V). The IR arm has been closed to recruitment. Previous interventions as of 29/06/2017: Participants will be randomised on a 1:1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR), ibrutinib plus rituximab (IR), ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V). Added 24/07/2017: FCR: fludarabine (oral), cyclophosphamide (oral) and rituximab (intravenous infusion). F (24mg/m2/day) and C (150mg/m2/day) are administered days 1‐5 and R is administered at 375mg/ m2 for day 1 cycle 1 and then at 500mg/m2 for day 1 for cycles 2‐6. Each cycle is repeated every 28 days and there are 6 cycles. IR: ibrutinib (oral) and rituximab. 6 cycles of R as per FCR. Ibrutinib (420mg) is administered daily for six years. I: ibrutinib monotherapy is administered as per IR I+V: ibrutinib + venetoclax (oral): ibrutinib is administered as per IR. Venetoclax is given daily from week 9 onwards in weekly dose increments (20mg, 50mg, 100mg, 200mg and 400mg) after which 400mg is administered for six years. Follow up: baseline, 9 months post randomisation then every six months until 7 years or disease progression. All participants will be followed up at least annually until death. Previous interventions: Participants will be randomised on a 1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR) or ibrutinib plus rituximab (IR). CONDITION: Topic: Cancer; Subtopic: Haematological Oncology; Disease: Leukaemia (chronic) ; Cancer PRIMARY OUTCOME: 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 OUTCOME: 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, as graded by CTCAE V4.03 , and determined by routine clinical assessments at each centre.; 9. Health‐related quality of life. The EORTC QLQC30 and EORTC QLQCLL16 will be used to measure participant assessed QoL prior to randomisation, at the end of treatment with FCR and R (for participants randomised to FCR or IR) or at 6 months post‐randomisation (for participants randomised to I or I+V), and then at 6‐monthly visits.; 10. Cost‐effectiveness. The SF12 and EQ5D will be used to produce quality adjusted life years (QALYs). NHS resource use and participants’ out of pocket expenses will be collected via the Case Record Forms, as well as health economics patient questionnaires. These will be collected prior to randomisation, at the end of treatment with FCR and R (for participants randomised to FCR or IR) or at 6 months post‐randomisation (for participants randomised to I or I+V), and then at 6‐monthly visits.; ; Previous secondary outcome measures as of 07/09/2018:; 1. PFS of I+V in comparison with I; 2. PFS of I in comparison with FCR; 3. Overall survival; 4. Proportion of participants obtaining undetectable MRD, as defined by IWCLL criteria; 5. Stopping of I‐containing therapy in MRD‐negative patients. Participants who have an MRD negative result in the peripheral blood at any timepoint between 12 and 30 months post‐randomisation will be eligible to stop treatment prior to the 6 years post‐randomisation timepoint if they confirm MRD negativity in the bone marrow.; 6. Time to MRD relapse for participants who stop I‐containing treatment based on MRD negativity and then go on to relapse at the MRD; 7. Response to therapy, as defined by IWCLL criteria. For each comparison, the best response for each participant at either 3 months post‐treatment with FCR, 9 months post randomisation (for participants randomised to I or I+V) or the end of treatment (for I or I+V) will be summarised by treatment group and overall. The proportion of participants achieving a Complete Response (CR+CRi) and an Overall Response (at least a PR) at any stage during the trial will be summarised by treatment arm; 8. Safety and toxicity. Safety analyses will summarise the AR, SAE, SAR and SUSAR rates per participant, by treatment received and overall for all participants randomised to stages II and III. ARs will be presented by CTCAE toxicity grade (V4.0.3). ; 9. Health‐related quality of life assessed using all domains of the EORTC QLQ‐C30 and the CLL‐specific module, EORTC QLQ‐CLL16.; 10. Cost‐effectiveness; ; Previous secondary outcome measures:; 1. Overall survival; 2. Undetectable minimal residual disease; 3. Response to therapy; 4. Health‐related quality of life ; 5. Cost‐effectiveness 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% withi