Background: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Combination\nimmunochemotherapy such as fludarabine, cyclophosphamide and rituximab is the standard first line therapy\nin fit patients, but there is limited evidence regarding the optimal treatment of patients after relapse. Ofatumumab as\nmonotherapy has been proven to be effective in the treatment of relapsed, refractory CLL, and as it is not myelotoxic,\nit is an ideal drug to combine with chemotherapy. However, the optimal dose of ofatumumab in this setting is not\nknown. The Chemotherapy plus Ofatumumab at Standard or Mega dose in relapsed CLL (COSMIC) trial will assess the\nefficacy and safety of standard and high (mega) doses of ofatumumab combined with bendamustine or a combination\nof fludarabine and cyclophosphamide to determine which, if either, schedule should progress to a phase III trial.\nMethods/design: COSMIC is a phase II, multi-centre, randomised, open, parallel group trial for patients with relapsed\nCLL who are not refractory to fludarabine-based chemotherapy. Participants will be randomised to receive either\nstandard dose or mega dose ofatumumab. Both doses will be given in combination with either bendamustine or\nfludarabine and cyclophosphamide chemotherapy backbone. The primary objective is to assess the proportion of\nparticipants achieving a complete remission following therapy with the two treatment arms (mega versus\nstandard), as assessed at 3 months post treatment. The treatment groups will be assessed independently to determine\nwhether the level of response is acceptable in relation to pre-specified criteria. If both treatment groups show an\nacceptable level of response, selection criteria will be used to determine which to take forward to a confirmatory\nphase III trial. A key secondary objective is to assess the dynamics of minimal residual disease (MRD) levels in\nrelapsed disease. Eighty-two participants are planned to be recruited from 18 research centres in the UK.\nDiscussion: Currently there is limited evidence regarding the optimal treatment of patients with relapsed or refractory\nCLL, and so suitable therapies are urgently needed. The COSMIC trial will identify whether ofatumumab given\nin combination with chemotherapy is safe and effective in this population, and will identify the optimal doses\nfor further investigation.
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