Thank you and I’d like to thank the organisers for the opportunity to present our work on the CLARITY trial. I present this on behalf of eleven centres and the research nurses, investigators and, of course, patients recruited throughout the UK over the last eighteen months. Chronic lymphocytic leukaemia or CLL is the most common leukaemia in adults; it occurs in about six patients per 100,000 are diagnosed with this disease and the conventional therapy for CLL is chemoimmunotherapy although the vast majority of patients will relapse after chemoimmunotherapy and until recently the treatment options were limited with most patients dying of the disease.
The last few years have shown a rapid development in our understanding of this disease, particularly that this disease is a driven disease with all patients having proliferation of the tumour cells with the pathways now being worked out through B-cell receptor signalling. Also every patient, virtually, having an abnormality of apoptosis, so the leukaemia cells don’t die, leading to the accumulation of the disease and resistance to treatment. Both of these pathways have led to novel agents which have been recently approved as single agents for the treatment of CLL. Ibrutinib is a targeted treatment against Bruton’s tyrosine kinase which was approved in 2013 as a single agent both in America and in Europe and is approved for all lines of therapy with CLL. It has clearly had a major impact on the outcome of patients with this disease, showing an overall survival advantage in many trials over the last few years. However, ibrutinib does not eradicate disease and patients remain on treatment indefinitely or until progression.
More recently, venetoclax has also been approved both by the FDA and EMA for resistant patients with CLL, so the indications are slightly different, slightly wider, in Europe. This drug has a very rapid effect which actually leads to tumour lysis syndrome which is very unusual in CLL but also leads to the eradication of minimal residual disease in some patients with a single agent which we know from chemotherapy trials is associated with prolonged survival.
The CLARITY trial is a feasibility trial where we recruited fifty patients with relapsed refractory CLL who had failed chemotherapy or with poor risk disease who had failed often targeted therapy into a combination study of ibrutinib and venetoclax, so targeting the two main pathophysiological pathways of this disease. The key endpoint, because MRD is associated with a better outcome, is the eradication of minimal residual disease at twelve months with the possibility of stopping these therapies rather than having indefinite treatment. I’ll show you the key secondary endpoints of six month MRD in the blood and marrow. Of course we’re also interested in the toxicity of this regime and we have a variety of exploratory endpoints in this phase II trial.
The study, we treat patients initially with ibrutinib to debulk the disease, they get two months of ibrutinib monotherapy which is usually well tolerated. We do bone marrows before and after that two months and then at two months we add venetoclax. We have an escalation for the first month to abrogate the tumour lysis syndrome and then bone marrows are performed at six months, twelve months and 24 months. In this trial of fifty patients we missed one bone marrow in all the patients so the patients have been very compliant with the treatment. If the patients are MRD, minimal residual disease, negative in the blood and marrow at six months they stop therapy after twelve months, six months of the combination. If they are negative at twelve months they stop therapy after 24 months because our modelling suggests that’s the most efficient way to get a prolonged, potentially indefinite, remission.
This is the group of patients, we recruited 54 patients, the majority are male, as we see in all CLL trials. They’ve all failed treatment but they’ve had a median of one prior line of treatment. 20% have got poor risk 17p and a quarter have 11q deletion which, again, is a poor risk feature in chemotherapy. The majority of patients, 81% of patients, had failed or had previously been treated with the two most commonly used chemoimmunotherapies most effective, FCR or bendamustine rituximab, with some patients being treated with a targeted treatment idelalisib. I should have said that patients were not permitted into the trial if they’d been exposed to either ibrutinib or venetoclax previously.
In terms of the toxicity, in terms of general adverse events, we saw neutropenia, which we see with venetoclax, and some GI toxicity which was largely grade 1 or grade 2. The particular AEs of interest, because we know these drugs have some side effects despite being targeted, we saw some bruising, so some subconjunctival haemorrhage and some bruising, neutropenia, which is associated with venetoclax, which responds to GCSF, as we heard in a previous talk, and otherwise very acceptable toxicity. There was a single case of tumour lysis syndrome which is similar to the 3% we’re seeing with venetoclax alone and that was managed successfully. It was actually in my sight and the patient re-escalated back onto treatment and is doing well. Seven patients had GCSF, as has been reported.
In terms of response, the key secondary endpoint is MRD eradication. We only have data out to six months for 38 of the patients where we have CTs, clinical assessments, peripheral blood and marrow. Of the patients 37% are MRD negative in the peripheral blood, 32% are MRD negative in the marrow and the trephine biopsy is normal in the vast majority of patients. In addition, if you look at the subsets of those patients who have failed chemoimmunotherapy and those who have had prior idelalisib, those patients seem to respond at a similar rate to the whole group.
In terms of IWCLL response criteria, which is a secondary endpoint, 47% of patients have achieved a CR or CRI and every patient has had an overall response which, for this group of patients, is impressive and that is similar across the patients who were refractory to chemotherapy or have had previous idelalisib.
In conclusion, we have demonstrated that the combination of ibrutinib and venetoclax can be given safely, we’ve had one single case of tumour lysis syndrome which is what we would anticipate from venetoclax as a single agent and that was manageable. The rest of the side effects were predictable and again were manageable. I haven’t shown you the data but no patients stopped treatment and only seven patients have had any interruption in treatment and only for a few days. We’re seeing even at this very early stage over 30% of patients achieving an MRD negative remission which was our target at the twelve month bone marrow stage with this combination. The principle of the Bloodwise Trials Acceleration Programme is that we can accelerate therapies and combinations into phase III to change practice and we’ve already modified our frontline FLAIR trial about six months ago to include this combination in a phase III frontline study which is currently recruiting very actively. Thanks for your attention.