The CAPTIVATE trial is a trial that is an evaluation of a combination of ibrutinib plus venetoclax for previously untreated patients with chronic lymphocytic leukaemia. The presentation at ASCO this year is an early planned analysis of safety and very early efficacy data in a limited number of the first several patients who have been treated on the trial. The design is for three months of ibrutinib monotherapy followed by a year of combination therapy with ibrutinib plus venetoclax. At the end of the year response assessment is done, including for minimal residual disease, and then patients are subsequently randomised for continued treatment or placebo, based on their MRD status at the end of the treatment. The data presented at ASCO this year is just the safety and for 14 run-in patients efficacy at the end of the year of combination therapy.
The treatment, the rationale for the treatment, is based on utilising the complementary activity of the two agents. Ibrutinib has made a fundamental difference in how we manage patients with chronic lymphocytic leukaemia, it’s highly effective at treating the disease and highly effective at long-term disease control. But patients don’t get in good, deep remissions with ibrutinib monotherapy. Ibrutinib is highly effective at shrinking lymph nodes but there is usually residual disease in the bone marrow. That’s in contrast to venetoclax which works by a different mechanism of action. Ibrutinib inhibits Bruton’s tyrosine kinase which is a signalling member of the B-cell receptor signalling pathway. Venetoclax inhibits BCL2 and is highly effective at inducing apoptosis in CLL cells where most patients are responding but there are patients who have residual disease with venetoclax and it’s usually in the form of enlarged lymph nodes. It’s highly effective at clearing bone marrow and blood of disease. So ibrutinib is effective at treating nodal disease, venetoclax is more effective at treating bone marrow and blood disease, so clinically they are complementary. There is also laboratory data that demonstrates synergy between the two agents and was the basis for proposing this combination.
Amongst the notes in the abstract I did notice tumour lysis syndrome risk. Can you tell us a bit about that?
Venetoclax inhibits BCL2 and when you block BCL2 it throws the cells into apoptosis and they rapidly die. So one of the risks with venetoclax is the tumour lysis that can be seen with initiation of treatment. Now, we’ve done a lot of work with venetoclax monotherapy and in development of the drug a strategy for initiation and escalation was developed which has made it very safe. It does require monitoring of patients during this initiation and escalation portion but it’s safe. On this trial patients received three months of ibrutinib first and that will downstage or downgrade the TLS risk prior to initiation of venetoclax. In fact, that’s what we saw with this trial where among the patients who were high risk for TLS 77% of them were downgraded into medium or low risk for TLS with just the three months of ibrutinib monotherapy. We didn’t see any clinical TLS in this trial with initiation of venetoclax. There were a couple of patients who had some laboratory changes consistent with TLS but nothing that was clinically relevant.
You mentioned that this is just the start. Can we expect to see any more information, say, at ASH this year or ASCO next year?
For sure at ASCO next year and ASH next year, this data will be presented at EHA next week or the following week. So, yes, this is an ongoing trial and we have 164 patients enrolled on this portion of the trial. Then the trial was modified to add an additional cohort of patients who are not going to be randomised when we have their MRD assessment, it’s just fixed duration of treatment of one year of combination. So there will be many more reports, we anticipate, with continued treatment and follow-up and response assessment on this study.
I look to hearing more about that soon then.