A Trial Looking at Ofatumumab for People With Chronic Lymphocytic Leukaemia Who Cannot Have More Intensive Treatment (RIAltO)

• Progression-free survival [ Time Frame: There are three pre-planned analyses of the PFS primary endpoint: end recruitment (approx 150 events); 300 events (after a minimum 12 months follow up for all patients), 400 events (after a minimum 24 months follow up for all patients) ] [ Designated as safety issue: No ]
  Calculated from the date of randomisation to the date of progression or death, or the censor date.
  
  

• Duration of response [ Time Frame: 6 years (after 2 years follow up of the last patient recruited) ] [ Designated as safety issue: No ]
  Response duration is defined as the time from when the criteria for partial or complete response are met until the first documentation of relapse or progression.
  
  
• Overall survival [ Time Frame: 6 years (after 2 year follow up of the last patient recruited) ] [ Designated as safety issue: No ]
  Overall survival is defined as the time from initiation of study treatment to death, irrespective of cause or subsequent treatment. Patients still alive at the time of analysis will be censored at the date last seen alive at last follow up.
  
  
• Time to treatment failure [ Time Frame: 6 years (after 2 year follow up of the last patient recruited) ] [ Designated as safety issue: No ]
  Time to treatment failure is defined as the time from initiation of study treatment to death, disease progression, or initiation of alternative treatment due to failure to achieve a complete or partial response to the study treatment.
  
  
• Toxicity [ Time Frame: 6 years (after 2 years follow up of the last patient recruited) ] [ Designated as safety issue: Yes ]
  Haematological toxicity will be reported in accordance with the 2008 NCI/IWCLL guidelines. Non-haematological toxicity will be reported in accordance with the current Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
  
  
• Treatment dose administered [ Time Frame: 5 years (assuming last patient in receives 12 cycles of treatment) ] [ Designated as safety issue: No ]
  The number of cycles of treatment and cumulative dose of individual drugs administered will be summarised for each treatment group separately and compared across treatment groups
  
  
• Quality of life [ Time Frame: 6 years (after 2 years follow up of the last patient recruited) ] [ Designated as safety issue: No ]
  Quality of life will be assessed using the EQ-5D; EQ-VAS; EORTC QLQ-C30 and EORTC QLQ-CLL16 questionnaires. To standardise the raw scores, they will be linearly transformed into 0-to-100 scores.
  
  
• Health Economic analysis [ Time Frame: 6 years (after 2 years follow up of the last patient recruited) ] [ Designated as safety issue: No ]

  The economic evaluation will take the form of a cost-effectiveness analysis with the differential cost of the alternative treatments will be related to their differential benefits in terms of quality-adjusted life years (QALYs). Incremental cost-utility ratios will be estimated based on QALY estimates.

  A range of uni- and multi-variate, as well as probabilistic sensitivity analyses will be conducted to assess the robustness of the analysis.

  The use of bootstrapping and cost-effectiveness acceptability curves will facilitate a measure of variability around cost-effectiveness estimates. Sensitivity analysis will be used to consider the importance of sources of uncertainty other than sample variation (e.g. unit costs, discount rates).

  A model-based extrapolation of the trial results will be performed to explore the impact of a longer analytic time horizon, and consideration of health outcomes on the treatment cost-effectiveness.

  
  
• Analysis of frailty and co-morbidity [ Time Frame: Baseline, 2 months post treatment ] [ Designated as safety issue: No ]
  Patients outcomes will be compared across patient subgroups defined by CIRS, performance status, Vulnerable Elders Survey-13, Groningen Frailty Index (GFI) questionnaires and the Timed 'Up and Go' test.
  
  
• Predictive value of biomarkers [ Time Frame: Baseline, every 6 months until 42 months from study entry, disease progression ] [ Designated as safety issue: No ]
  Patient outcomes will be compared across patient subgroups defined by clinical (e.g. age, sex, stage) and laboratory (e.g. chromosomal, abnormalities, IGHV mutation status, TP53 mutation status).
  
  
• Response [ Time Frame: Baseline; 2 months post treatment; 6 months post treatment ] [ Designated as safety issue: No ]
  Response following initial therapy will be assessed in accordance with the revised (2008) NCI/IWCLL response criteria applicable to CLL. Minimal residual disease will be assessed by multicolour flow cytometric analysis of bone marrow aspirate samples taken 2 months after completing treatment and of blood samples taken 2 and 6 months after completing treatment.
  
  

Chlorambucil (Chl) has been the mainstay of CLL treatment for half a century. However, frontline treatment has improved considerably over the last decade, first by the advent of fludarabine plus cyclophosphamide (FC), and more recently by the addition of the anti-CD20 antibody, rituximab, to FC. Although FC-based regimens are considerably more effective than Chl, they are also associated with greater toxicity which makes them inappropriate for less fit patients. This is an important consideration, given that CLL predominantly affects older people who tend to have more co-morbidity. Although a single-arm phase II study (Roche MO20927; NCRI CLL208) has shown that R-Chl is safe and effective, there are no phase III data proving the benefit of adding an anti-CD20 antibody to Chl. This question is currently being addressed by a phase III RCT of Chl with or without ofatumumab (GSK OMB110911 / COMPLEMENT-1 / NCRI CLL7). Ofatumumab is a fully human anti-CD20 antibody that binds to an epitope distinct from that of rituximab and produces more complement-dependent cytotoxicity. The RIAltO trial is a direct follow-on to the NCRI CLL7 phase III RCT trial in less fit patients and therefore the Ofatumumab dose has been selected to mirror the regimen used in that trial.