I managed to attend my first Committee meeting yesterday. I went to London to meet with other CLL experts to discuss the forthcoming British CLL trials.
If anti-CD20 antibodies add so much to CHOP, CVP and now FC, does it work for other forms of chemotherapy and for other anti-CD20 antibodies? There are several trials taking place in various countries to answer these questions. One such is the use of FC plus or minus Ofatumumab. This is having some difficulty getting off the ground. It intends to recruit 352 patients from 67 centers in 15 different countries. So far it has only recruited 30 patients. In the UK this will be an unpopular trial because the F and C have to be given intravenously whereas we give both orally. Oral fludarabine has been approved for use in the USA by the FDA. Of course the oncologist is paid less for giving out tablets than for giving an infusion, so we wait to see if it will prosper.
But another reason for its unpopularity may be the phase II study organized by Genmab. Patients in this open label study were randomized into two treatment groups. Each patient was to receive one infusion of 300 mg of ofatumumab in combination with FC followed by 5 monthly infusions of either 500 or 1000 mg of ofatumumab in combination with FC. Disease status was measured every 4 weeks until week 24 and every 3 months thereafter until disease progression or 24 months. Treatment response was assessed according to the 1996 National Cancer Institute Working Group guidelines by an Independent endpoints Review Committee. Patients not having
progressed on their disease at 24 months will be followed for disease progression at 6 month intervals until 60 months.
A total of 61 patients were treated in the study. The complete remission rate was 32% in patients who received 500 mg of ofatumumab (n=31) and 50% in patients who received 1000 mg of ofatumumab (n=30). The overall response rate was 77% in the 500 mg treatment group and 73% in the 1000 mg treatment group. Although these figures age good, they are not as good as have been achieved with FCR. Now this is not a head-to-head comparison with FCR and we know that it is dangerous to compare one phase 2 trial with another, but it does look likely that FCO will not be superior to FCR, so unless it has other advantages it doesn't look to be replacing rituximab any time soon. Of course when the trials mature it may turn out to have other advantages. The problem at the moment is that FCR is going to be a hard act to beat. This is one reason for going for MRD negativity as an end-point, as this is one area where FCR might be beaten.
Yet another reason for its unpopularity is that the comparison arm, FC, is no longer standard of care. The only possible trial is FCO versus FCR which no-one is going to fund.
Two current trials in the UK which might add something are ADMIRE and ARCTIC. ADMIRE stands for ADdition of Mitoxantrone to Improve REsponse. This is a randomized phase 2 study the main aim of which is to see whether adding mitoxantrone to FCR gives a deeper response - does it produce more MRD negativity? If it does it will be exopanded into a phase 3 trial with progression-free survival as primary end-point. (Just to remind readers about trials: phase 1 determines the dose of a drug it is safe to give, phase 2 determines whether it has an effect and phase 3 determines whether it improves survival compared to standard treatment.) 218 patients recruited over 18 months are needed for the phase 2 but more will be needed if it is expanded into a phase 3.
ARCTIC stands for Attenuated dose Rituximab with ChemoTherapy In CLL. This is the trial that tests out the 'shaving' hypothesis. Is it true that most of the rituximab that we give is ineffective because the first 100mg removes the CD20 from the surface of the cells? The comparison is between FCR and FCM-miniR. The endpoints are the same as for ADMIRE and 206 patients will be recruited in 18 months. Again it will be expanded into a phase 3 trial if the response rates are equivalent to FCR. The advantage of this regimen are completely a matter of cost. It is being funded not by Big Pharma, but by the NHS to see whether there are cheaper ways of doing the same thing.
A Phase 2 study of chlorambucil plus rituximab has been completed and an interim analysis of the first 50 patients will be presented at ASH. It shows an overall response rate of 84%. Although the CLL4 trial treated rather younger patients, it had a chlorambucil only arm and the response rate for these was 66.7%. So the the next move will be a phase 3 trial looking at the effect of adding rituximab in patients treated with chlorambucil. 100 patients have been recruited in total.
A randomized phase 3 trial comparing chlorambucil with chlorambucil plus ofatumumab is recruiting well with 114 / 444 patients already recruited. A quarter of these will be from the UK.
A further chlorambucil plus antibody phase 3 study with 800 patients is about to start. It will have 800 patients and compare chlorambucil alone with the addition of rituximab or the new Roche antibody GA-101.
It looks like GA-101 and ofatumumab will be competing for the same market.
For patients who fail to achieve MRD negativity, a consolidation stage of treatment is necessary. This is best done with alemtuzumab. A Phase 2 trial is attempting to recruit 54 patients. So far 44 have been recruited and there are another 14 patients registered. The trial closes in March 2010. This is a preliminary study to determine whether using alemtuzumab in this way is safe and efficacious. Analysis of the first 24 patients showed that 18 became MRD negative. Remember a similar CALGB trial showed 5 deaths from infection with this strategy and a German trial had to be stopped because of pancytopenia. It is clear that this sort of approach is littered with danger. So far there have been two deaths in patients who didn't live long enough to get the treatment. There have been 19 serious adverse events in this trial which include a number of viral infections and reactivations. I think there was a single death from parainfluenza - always a hazard with immunodeficient patients. This trial will proceed to a randomized phase 3 comparison between no further treatment and alemtuzumab consolidation if the safety profile is satisfactory.
For the treatment of high risk disease we are looking at the possibility of alemtuzumab, dexamethasone and Revlimid. We have switched from high dose methylprednisolone to dexamethasone partly because it is oral but mainly because of glucocorticoid effects like muscle wasting and hypertension which are less with dexamethasone. The HDMP + Campath trial was presented at EHA in the summer and will be published shortly.
Another approach to high risk disease will be the combination of Revlimid and Dexamethasone without Alemtuzumab.
For patients with stage A disease we are dividing them into those with two or more adverse markers, who will be started immediately on Revlimid, even though they do not meet the criteria for treatment. For those without high risk markers they will be given two weeks of broad spectrum antibiotics against the possibility that like marginal zone lymphoma, CLL is initiated by bacterial infection.
All patients in all trials will have their cells banked and categorized according to prognostic markers. Untreated patients will be followed in the pan-European data-collection study.
Finally, for Richter's syndrome, a trial of CHOP plus ofatumumab with antibody maintenance is to be started shortly.