New Clinical Trials

I was at the UKCLL Forum Clinical Trials Meeting yesterday. Here are some of the trials up and running or in development in the UK.

CLL6 is in preparation. It needs funding from the Health Technology Assessment Board. It asks a question about cost, namely, do we need such a large dose of rituximab. It compares FCR with FCmini-r + mitoxantrone in a non-inferiority study. This is a randomized phase II study. The dose of rituximab in mini-r is 100mg as opposed to 500mg/sq meter for FCR. Such a small dose can be given quicker and save time an money in the hospital. With small doses there is also the possibility of sc delivery which also saves money.

The use of mini-r derives from the work of Ron Taylor about which I have reported previously. Antigen shaving means that higher doses of rituximab have no CD20 to latch on to. If FCr+M is not inferior to FCR in response rate then a three way randomization of FCR v FCr+M v FCRM would be undertaken. Obviously the pharmaceutical companies will not fund a mini-r trial in case it is as good as full doses and their sales were gut to a fraction of present sales.

Since the German trial shows FCR to be better than FC (although this is from the Roche website and not from a peer reviewed publication) trials with FC as the comparator are non-starters now. However we do not expect publication of the German CLL8 until ASH this year and peer review won't happen to 2009. Therefore NICE will not pronounce until 2010/11. British patients will therefore not get rituximab until then.

As a consequence Roche have offered to fund a FCR v FCRM trial in the UK (using oral FC). This would enable British CLL patients to get free rituximab until NICE pronounces. It could also be seen as an interference ploy by Roche to prevent the mini-r trial from accruing. A cynic might suggest that Roche might be lobbying HTA to stop the funding for mini-r. There is certainly a message coming down from National Cancer Research Institute (NCRI) that they want to encourage participation in industry sponsored trials. Industry also has an interest in demonstrating that FCR with oral FC is as good as with iv FC.

In this context I ought to report that Pete Hillmen's phase II study showed that FCM-R was better than FCM in terms of response rate and quality of response. Historically, we know that FCM produces equivalent responses to FCR is separate phase II trials.

On the question of trials for older patients and those with co-morbidities, we looked at teh possibility of bendamustine trials. However, we thought that this was rather like going back to driving a Trabant when you had previously driven a Ford Focus. We decided to stick with chlorambucil, though given at a proper dose of 70mg/sq m/month rather than the 40mg/sq m/month used in American trials. Roche is supporting a phase II trial using this dose of chlorambucil with rituximab in conventional doses. 50 patients will be recruited in a maximum of 12 months. So far 10 sites are actively recruiting with 11 patients registered. CLL7 might be a randomized phase III comparing Chlorambucil plus or minus rituximab, but GSK have offered an alternative randomized phase III using ofatumumab (HuMax CD20) instead of rituximab.

CLL8 looks at the Campath consolidation question. The aim of this trial is to determine the rate of achieving MRD negativity as determined by 4 color flow cytometry in patients with low levels of MRD following conventional therapy or who relapse at MRD level after a previous MRD negative remission; and to assess the safety of alemtuzumab in the MRD positive setting. The recent CALGB trial had 5 deaths after Campath which has put the wind up Bayer, who bought Schering AG. However, this degree of toxicity is anomalous and may be a reflection on the community oncologists entering patients in that trial.

MRD positive patients will receive alemtuzumab 3 times a week for a total of 6 weeks. Patients whose CLL has disappeared will stop treatment. Patients whose CLL levels have not changed since before the start of treatment will stop treatment. Responding patients who have detectable CLL at the end of 6 weeks will continue treatment for 6 more weeks. MRD negative patients will be monitored every 3 months until they become MRD positive at which point they will be eligible to receive treatment with alemtuzumab.

Up to 54 patients will be recruited over a two year recruitment period and so far 15 patients are registered.

CLL206 is a phase II trial of Campath and high dose methylprednisolone in 17p deleted cases. There was a high MRD negative response rate and this will come to publication shortly. CLL10 asks a Revlimid question in the same group. Even MRD negative patients relapse so Revlimid maintenance will be examined in this study.

CLL203 ask a Revlimid question in high risk p53 or ATM deleted patients. The principle aims of the study would be to determine 1. Response (according to 2008 IWCLL criteria plus MRD eradication, 2. Safety and dosing schedule, 3. Time to next treatment. This question has been a thorny question with us. We have looked at the possible use of FC, FCR, rituximab, alemtuzumab and now Revlimid in this context. The figures for this group are so bad, however, that we feel that something must be done. Rituximab does not depress the immune system nor cause DNA damage - though it does have other unpleasant side effects.

We are also considering an FC plus or minus ofatumumab trial in relapsed disease. This would be commercially sponsored and therefore iv FC, which is a disadvantage, but would cost nothing and give us something to offer until NICE looks at FCR. It competes directly with the FCR plus or minus luxililimab trial, but this is not generally popular in the UK.