Advances in treatments for haematologic malignancies from the Sarah Cannon Research Institute presented at ASH 2012 (2/5)
Dr Ian Flinn – Sarah Cannon Research Institute, Nashville, USA
Give us an overview of your phase II trial of ofatumumab (OFA) for older patients and patients who refuse fludarabine-based regimens.
Ofatumumab is a new generation anti-CD20 monoclonal antibody that in the laboratory looks like it has enhanced activity over rituximab and it was approved for patients with refractory chronic lymphocytic leukaemia. We know that most drugs that we use are better off in the front line than when given when other things are failing. This also has to be kept in the context that in older patients there’s really no one good therapy for patients, really, above 65 or 70. Some of the fludarabine trials did not show an advantage in that patient population where fludarabine given in younger patients, especially in combination, is very effective. So we are seeking to develop a well-tolerated effective therapy for older patients.
I must say my colleague, John Hainsworth, about a decade ago at Sarah Cannon conducted a trial in this very same patient population with rituximab and he showed with rituximab it was well tolerated although the response rate was about half of patients and the progression free survival was about 60% at one year and we were hoping to improve upon that. So we conducted this trial with ofatumumab given as a stepped up fashion, initially the doses were 2000mg after a first dose of 300mg and that was given weekly until they reached a maintenance phase. That was given weekly for eight weeks and then there was an evaluation and then those patients that were responding, or at least had stable disease, could go on to receive maintenance therapy with ofatumumab every eight weeks for up to two years. That was the original trial and we had some interesting results. I think that the overall response rate was high; when we looked at the response rates using the new criteria compared to the criteria that the antibodies in the past were all judged by, it jumped up a lot. So we were seeing approximately 80% overall response rate when we used the same criteria that all the other antibodies were judged by in the past.
That was an interesting finding and then there was also this notion that maybe we don’t have to give so much ofatumumab, maybe we could back down on that dose. There are still a lot of questions about what the right dose is. So we accrued a second cohort; the first cohort was 44 patients, the second cohort of a bit more than 30 patients and we used 1000mg in that very same design.
What were the findings and what are the next steps in clinical research?
The interesting finding to me was that there was a decrease in response rate. Now you have to take this with a little bit of a grain of salt because these patients were older so the median age was 75 in that second cohort; they had more high risk cytogenetics, there was a patient that was 93 years old. So we certainly did not cherry pick the patient population, this is a very real world older patient population. The first cohort, the median age was about six years or so younger so they’re not completely the same but the outcome did look like it was better with the higher dose. The thing I think is interesting about this is this is good regimen for people but it’s going to serve as the backbone for future trials through Sarah Cannon for this patient population. We’re about to open a new trial combining this backbone with lenalidomide; we’d love to subsequently do trials with one of the new B-cell receptor pathway molecules which don’t have all the same toxicities that we see with regular chemotherapy.
How successful was trial accrual?
This was one of the most popular trials I’ve ever conducted because the treating physicians and the patients really, especially in this age group, just do not want to receive any kind of standard chemotherapy and so accrual was brisk, very brisk, in fact probably the fastest accrual of any clinical trial I’ve ever conducted in my career.