Matthew S. Davids, MD, MMSc, from Dana-Farber Cancer Institute, discussed his phase I/II study of duvalisib (Copiktra) in combination with venetoclax (Venclexta) for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, held December 7-10, in Orlando, Florida.
So, one of the abstracts that I’m very excited about at this meeting is our study of duvalisib with venetoclax for patients with relapsed/refractory CLL and SLL. This is a phase I/II study, and at this meeting my colleague, Dr. Jennifer Crombie, has presented the phase I portion of the study.
The design of the study takes patients who are relapsed/refractory after at least 1 prior line of therapy, which actually in many cases on this study was a BTK inhibitor like ibrutinib (Imbruvica), and treats them just with 1 week first of duvalisib and then introduces venetoclax in combination after that. And we used a fairly standard venetoclax ramp-up, although at the beginning we started with a lower dose of 10 mg of venetoclax just to be a bit cautious because there was a theoretical concern about a drug-drug interaction between these two drugs. And actually, 1 of the end points of the study was to do close-pharmacokinetic analysis to actually figure out if that was the case. So, at this point, we treat the patients for up to 12 months of combination therapy. At the end of that 12-month period they have a full disease assessment. That includes testing of the bone marrow, along with minimal residual disease. And if patients are in complete remission with undetectable MRD in the bone marrow, they’ll stop both drugs and go on observation. If patients still have residual disease or if they’re in a partial remission, they still stop the duvalisib and they continue on the venetoclax as a monotherapy. And that was done due to some of the longer-term side effects that we can see with PI3-kinase inhibitors, so we tried to minimize that exposure and really maximize the benefit of the PI3-kinase inhibitor with the venetoclax.
So, so far, we’ve treated 12 patients and the toxicity profiles of the 2 drugs have looked fairly favorable. We do see some of the usual toxicities we might expect from either drug. We saw some diarrhea and colitis with the duvalisib, we saw a fair amount of neutropenia in the study as we might see with venetoclax, but not a lot of infections and the neutropenia was usually manageable with growth factor support. We were able to escalate up from an initial dose level of 200 mg of the venetoclax up to 400 mg of venetoclax, and that was safe to tolerate, so we moved on to phase II which is now open and we haven’t presented those results yet but we’re excited to see how that develops. What we were able to show at this meeting was some very preliminary efficacy data from the phase I portion just in these 12 patients, and already we’re starting to see complete remissions and some patients with undetectable MRD, although we’ve only had 3 patients get to the 12-month mark yet. So, it’s very early with efficacy, but certainly what we’re seeing looks promising. And in the phase II portion, in addition to having a CLL cohort, we’re also going to have a separate cohort of patients with Richter’s syndrome who are going to be treated with the same regimen. We’ve had some preclinical data from a group in Italy that’s shown very nice data combining these two drugs in a model of Richter’s syndrome, and we’re hoping that’s going to translate into efficacy for our patients. So, we’re excited for the study moving forward, it’s openly accruing, and so hopefully we’ll be able to accrue that quickly and report it again soon.