Umbralisib, ublituximab and venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia

Dr Paul Barr - Wilmot Cancer Institute, University of Rochester Medical Center

This morning at one of the CLL sessions I presented the results of a phase I/II study combining a novel PI3K inhibitor with a novel anti-CD20 along with the BCL2 inhibitor venetoclax. So it was a three drug combination of umbralisib, ublituximab and venetoclax, the strategy being to use these three agents to achieve deeper remissions for CLL patients with relapsed disease using a shorter duration of therapy which, while we have many new agents, is still an unmet need for this class of patients. So the phase I results essentially showed us that the recommended phase II doses were well tolerated at the typical doses and frequency that we would normally use. Overall we administered three cycles of umbralisib ublituximab to debulk patients then combined venetoclax and umbralisib for nine additional cycles, the total therapy being twelve cycles or just about one year.

Again, safety-wise, the results suggested manageable myelosuppression, manageable GI toxicities and, importantly, no evidence of tumour lysis syndrome or laboratory tumour lysis. So, all in all, patients seemed to tolerate the treatment very well.

Efficacy speaking, the goal was really to induce deep remissions with the shortest possible therapy. So over the twelve cycles we monitored CTs along the way and by the end of three cycles the majority of the patients have responded, by the end of seven cycles all patients had achieved an objective response and at the end of the twelve cycles nine patients have only finished the entire one-year treatment plan so far but of those nine patients four had achieved a complete response and five a partial response.

Maybe one of the most important points in terms of efficacy was the MRD detectability rate. All nine were undetectable in the peripheral blood and seven of the nine were undetectable in the bone marrow. So putting it all together it really does look like a manageable regimen that’s not overly toxic, that only takes a year to give. The efficacy very early on but looks very promising.

So with this in mind enrolment continues to this phase I/II study. We have expanded it to ensure that we are treating a sufficient number of patients that had been previously exposed to BTK inhibitors. We’ve also expanded it to investigate the regimen in Richter's transformation as well as mantle cell lymphoma.

We used a flat dose of the antibody ublituximab, 900mg, and in the phase I portion we administered it five times over the first three cycles. The venetoclax dosing was standard, standard five week ramp-up up to 400mg. The umbralisib dose, though, the agent that was explored in the phase I, it was well tolerated at 600mg, well tolerated at 800mg, ultimately leading us to conclude that the 800mg dose would be the recommended phase II dose as it is in other studies. So we’re really using the standard doses and frequency that have been used in other clinical trials.

Acknowledging that it’s very early on, I really think we’re seeing pretty promising tolerability and efficacy, again acknowledging that we need to see the long-term outcomes, the progression free survival. But, having said that, we know venetoclax is already a standard of care in the relapsed refractory setting and potentially the first line setting. So there’s a lot of potential for this three drug combination to build on what venetoclax has already taught us, that it can be a very efficacious treatment regimen using limited duration therapy. So in the short term this really could change how we treat relapsed refractory patients and we’re anxious to explore it in other areas further.