FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab

INTERVENTION: Trade Name: Fludara Product Name: Fludarabine (oral) Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Fludarabine phosphate CAS Number: 75607‐67‐9 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: equal Concentration number: 24‐ Product Name: Fludarabine (IV) Pharmaceutical Form: INN or Proposed INN: Fludarabine phosphate CAS Number: 75607‐67‐9 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: equal Concentration number: 25‐ Product Name: Cyclophospamide (oral) Pharmaceutical Form: Tablet INN or Proposed INN: Cyclophosphamide monohydrate CAS Number: 50‐18‐0 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: equal Concentration number: 150‐ Product Name: Cyclophosphamide (IV) Pharmaceutical Form: Powder for solution for injection INN or Proposed INN: Cyclophosphamide monohydrate CAS Number: 50‐18‐0 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: equal Concentration number: 250‐ Product Name: Rituximab Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Rituximab CAS Number: 174722‐31‐7 Concentration unit: mg/m2 milligram(s)/square meter Concentration type: range Concentration number: 375‐500 Product Name: Ibrutinib Pharmaceutical Form: Capsule, hard INN or Proposed INN: Ibrutinib CAS Number: 936563‐96‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 140‐ CONDITION: Chronic Lymphocytic Leukaemia (CLL). ; MedDRA version: 17.1 Level: PT Classification code 10008958 Term: Chronic lymphocytic leukaemia System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15] PRIMARY OUTCOME: Main Objective: The principle research question this trial aims to answer is does ibrutinib given in combination with rituximab (IR) improve the length of time that patients are progression free when compared to fludarabine, cyclophosphamide and rituximab (FCR) in patients with previously untreated chronic lymphocytic leukaemia (CLL). Primary end point(s): Progression free survival: 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. Secondary Objective: To assess and compare for each treatment group:; • Overall survival; • Proportion of participants with undetectable minimal residual disease (MRD) (as defined by IWCLL criteria); • Response to therapy (as defined by IWCLL criteria); • Safety and toxicity; • Health related quality of life; • Cost‐effectiveness; Timepoint(s) of evaluation of this end point: An interim analysis will be carried out on the primary endpoint when half the required number of events have been observed (191) in the FCR and IR arms combined (likely to be after the trial has closed to recruitment). Final analysis on both primary and secondary endpoints will be performed when at least 382 events are observed and there is sufficient follow‐up data. This will be approximately 4 years after the trial closes to recruitment. Survival analyses will also be updated as appropriate. SECONDARY OUTCOME: Secondary end point(s): 1. Overall survival: 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.; ; 2. Minimal residual disease: A negative MRD is defined as the presence of <0.01% CLL cells in the bone marrow. MRD will be assessed for negativity at 3 months post‐therapy, 12 months post‐randomisation and then at each follow‐up visit where MRD is assessed (annually for the FCR arm and 6 monthly for the IR arm from 12 months post‐randomisation).; ; 3. Response: Response criteria are defined by the standard IWCLL criteria. Response to therapy will be assessed at 3 months post‐therapy with FCR or R and then again for participants randomised to IR at the end of therapy with ibrutinib.; ; 4. Safety and toxicity: Reported based on adverse events, as graded by CTCAE V4.03 , and determined by routine clinical assessments at each centre.; ; 5. 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, and then at 6 monthly visits.; ; 6. 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, and then at 6 monthly visits.; Timepoint(s) of evaluation of this end point: 1. Overall survival: Time from randomisation to date of death.; 2. Minimal residual disease: Assessed for negativity at 3 months post‐therapy, 12 months post‐randomisation and then at each follow‐up visit where MRD is assessed (annually for the FCR arm and 6 monthly for the IR arm from 12 months post‐randomisation).; 3. Response: Assessed 3 months post‐therapy with FCR or R and then again at the end of therapy with ibrutinib.; 4. Safety and toxicity: Reported on an ongoing basis and based on adverse events as determined by routine clinical assessments at each centre. ; 5. Quality of life: Prior to randomisation, at the end of treatment with FCR and R, and then at approximately 6 monthly intervals.; 6. Cost‐effectiveness: Prior to randomisation and then at 6 monthly intervals.; INCLUSION CRITERIA: • At least 18 years old. • Maximum age of 75 years old. • B‐CLL with a characteristic immunophenotype, including small lymphocytic lymphoma • Binet’s Stages C, B or Progressive Stage A • Requiring therapy by the IWCLL criteria in that they must have at least one of the following: 1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia. 2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy. 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 30x109/L 5. A minimum of any one of the following disease‐related symptoms must be present: (a) Unintentional weight loss more than or equal to 10%