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Recommended Phase 2 Dosing of Venetoclax Plus DA-EPOCH-R for B-Cell Lymphomas

 

Sarah Rutherford, MD, Weill Cornell Medicine, New York, NY, discusses the results from a phase 1 study, which evaluated the combination of venetoclax with DA-EPOCH-R in aggressive B-cell lymphomas.

Transcript

My name is Sarah Rutherford, and I'm Assistant Professor of Medicine at Weill Cornell Medicine, with a focus on lymphoma patient care and research.

I am going to present to you the results of a clinical trial of the BCL‑2 inhibitor, venetoclax, plus dose‑adjusted EPOCH‑R as initial therapy for aggressive B‑cell lymphomas, which was presented at the ASCO 2020 meeting.

A bit of background is that dose‑adjusted EPOCH‑R is a standard treatment that is used to treat aggressive B‑cell lymphomas, which are newly diagnosed, but is often inadequate. In particular, in patients who have rearrangements or overexpression of something called BCL‑2, this can be found in 2 subtypes that are called double‑hit lymphomas and double‑expressor lymphomas.

We wanted to investigate the combination of venetoclax, which is a BCL‑2 inhibitor, with dose‑adjusted EPOCH‑R.

This was a phase 1 study, so the goal was for us to assess the toxicity, the tolerability, and to determine a maximum tolerated dose of this combination, with the goal of then continuing on, particularly in those subtypes that I mentioned. This study enrolled patients with a variety of different aggressive B‑cell lymphomas, not just the double‑hit and double‑expressor lymphomas that I mentioned.

We looked at various treatment schedules. Ultimately, investigators opened a cohort of the drug called venetoclax of 600 mg on a 5‑day schedule with every cycle of chemotherapy. This is a treatment that goes on for about 18 weeks. Dose‑adjusted EPOCH‑R is given every 3 weeks. The oral drug, venetoclax, was given for varying days with each cycle of dose‑adjusted EPOCH‑R.

Ultimately, we determined that the phase 2 recommended dose was a 600 mg dose of venetoclax on a 5‑day schedule. I wanted to note that we had a particularly high‑risk patient population. The majority of patients had stage 2 to 4 disease, or in particular, 23 out of 30 had stage 3 to 4 disease.

There are actually 15 out of the 30 patients on the trial were diagnosed with double‑hit lymphoma, which I've mentioned already tend to be a particularly more aggressive form of lymphomas that can be hard to cure with standard chemo immunotherapy.

We found that the most common adverse events were decreased blood counts, fatigue, and nausea, which are often expected with a dose‑adjusted EPOCH‑R backbone of chemotherapy. We did find a couple of adverse events that we want to pay particular attention to in forthcoming clinical trials.

That was febrile neutropenia was more common in this trial than maybe seen in just a dose‑adjusted EPOCH‑R regimen. Not surprising, we were adding an additional therapy, but still want to look at that further.

We did find that 8 out of the 30 subjects had gastrointestinal serious adverse events. One of those patients came off the study early because of this. But the majority of them result with medical management without any aggressive measures having to be taken. Again, those 2 adverse events will be watched closely in forthcoming trials.

We had some exciting response data coming out of this trial. Of 30 patients, we had complete response in 28 out of the 30, so that was a 93% complete response rate and partial response in 1. We're having an overall response rate of 97%.

Then, in particular, in the double‑hit patients, which I mentioned were 15 out of the 30, there was an overall response rate of 93% and a CR rate of 87%. This is a response based on intention to treat.

The next steps with the study are already underway, using the dosing regimen that we have determined to be well tolerated in this patient population. The Alliance 51701 study is a Phase 2 to 3 clinical trial, venetoclax, plus chemo immunotherapy for MYC and Bcl‑2 double‑hit and double‑expressing lymphomas.

They mean to enroll 272 patients, which will be randomized to getting the standard backbone chemotherapy that that category would get. The double‑hit lymphoma patients will get dose‑adjusted EPOCH‑R, and the double‑expressor lymphomas will get R‑CHOP. Then they will be randomized to either getting venetoclax as well with those combinations. The primary endpoint is progression‑free survival.

Jeremy Abramson, who I worked closely on the current trial with, is running that. It is actively enrolling.

I'm very excited about this combination. I think that investigators and the physicians who treat patients with these diseases should look to getting these patients with high‑risk lymphomas on this clinical trial that's open, if available. Then also look to the future as this trial eventually becomes reported as potentially a very promising combination for aggressive B‑cell lymphomas

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