The importance of randomisation in evaluation of treatments for Acute Myeloid Leukaemia Lessons from the UK NCRI AML16 and LI-1 trials Ian Thomas, Senior Trial Manager Centre for Trials Research, Cardiff University Prof Robert Hills, Prof Nigel Russell, Dr Mike Dennis Put all authors on and bold yourself.

Randomise or not: decision Know your disease Homogeneous/heterogeneous? Outcome Do you expect good or poor outcome? Is the standard treatment suitable for randomisation? Cheap, well-defined?

To not randomise? Single arm trials are Smaller, faster, cheaper May be only option in a very rare disease Valuable if outcome is known (e.g. no long term survival at all) But what if your population is heterogeneous?

Case study: Pick a Winner Numerous novel agents may be compared to standard treatment Efficient design Agents are compared within a randomisation arm against standard treatment Robust data Novel agents not compared against each other, or against ineligible control patients Multiple ‘stand-alone’ trials within a trial Early look at whether remission likely to be improved sufficiently

Non-intensive approach to AML Findings from AML14 Low-dose cytarabine (ara-C) standard of care Improved survival down to inducing remissions However, no remissions in adverse risk patients AML16 and LI1 Randomise novel therapies against low dose cytarabine Look for improvement in survival But if no improvement in remission, survival benefit unlikely

Pick a Winner history

Control arm outcomes Novel treatment CR rate (%) 1 year overall survival A 18% 24% B 8% 28% C 19% D 22% 30% E 26% F 25% 34% G 29% 27% H 31% I 33% 37% NB Equivalent eligibility criteria

Scenario A new treatment has a remission rate of 22% Compared to arms A, B, C, E this would be an improvement But compared to arms D, F, G, H, I it would not be promising (null or worse) Without knowing the patient details, we can’t interpret a single arm reliably

Conclusions In poor-risk patients, estimate of outcome can be conducted early With a proven surrogate for your outcome In heterogeneous population, control arm may vary over time Different eligibility criteria can be accommodated Little option but to randomize in this AML population Contemporaneous analysis is required Phase II trial data may contribute to Phase III evaluation