Devimistat Could Have Practice-Changing Potential in Burkitt Lymphoma

Ariela Noy, MD

For patients with either Burkitt lymphoma/leukemia or high-grade B-cell lymphoma who have relapsed on multiagent therapy, devimistat (CPI-613), a novel compound targeting mitochondria has the potential to improve outcomes and increase response rates in an ongoing phase II trial.

Devimistat is an intravenous (IV) lipoate analog that can shut down the mitochondria, which produces energy and can lead to cancer cell growth. Cancer cells are more susceptible than healthy cells to this turn-off process.

In the multicenter, open-label, single-arm, phase II trial (NCT03793140), devimistat is given as induction therapy at 2500 mg/m² for days 1 to 5 for the first 2 cycles, followed by maintenance devimistat on days 1 to 5 for all following cycles in patients with relapsed/refractory Burkitt lymphoma/leukemia or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. The primary endpoint is overall response rate (ORR).

Devimistat has an FDA orphan drug designation for the treatment of patients with Burkitt lymphoma, a population that currently has no standard second-line therapeutic option. The agency also granted orphan drug status to devimistat for the treatment of patients with peripheral T-cell lymphoma, pancreatic cancer, acute myeloid leukemia, and myelodysplastic syndrome.

In an interview with OncLive, principal investigator Ariela Noy, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the phase II trial of devimistat in Burkitt lymphoma and other lymphomas, and described the unique mechanism of action of the agent.

OncLive: Could you describe the patient populations that are being enrolled on this trial?

Noy: In all of these entities, they are considered high risk in the sense that these are high-grade tumors. Patients coming in have to be very aggressively treated and their time frame from treatment initiation is traditionally very short. It is considered a lethal disease if it’s not treated quickly.

With that in mind, the paradox is that in these same patients with Burkitt lymphoma, there is the standard treatment approach, which has been vetted in nonrandomized trials. It is all multiagent therapy, it’s very intensive treatment, and its success rate is about 80%. The problem is that the patients who relapse or have primary disease have almost no treatment options, so it’s almost an anecdotal case of someone who has relapsed and survived. In 25 years, I have only seen a few people who have made it through relapse; it is extremely uncommon.

That is due in part that you have already exhausted all of the different treatments that you can give upfront because you’re giving all these different drugs [at once], so you don’t really have a lot of options at that point. It is merely tragic. The disease is also split up, so you have some older patients, but many of the patients are younger, so it’s very devastating to watch someone succumb to this disease.

Similarly, there is an issue with double-hit and triple-hit lymphomas. Burkitt lymphoma has a driver called c-Myc, and that is definitional to Burkitt in that it also drives all of these other genes. In double-hit and triple-hit lymphomas, you have a translocation other than c-Myc; you also have a translocation of BCL2 and BCL6. That combination is like putting your foot on the gas and letting the brake never be employed. Therefore, [it] proliferates these cancer cells, but they don’t ever die.

This is a relatively recent addition to the categories of lymphomas, and prospective studies have not really been done for double-hit and triple-hit lymphomas. There are mostly retrospective analyses—for patients who are having a poor outcome, we can look retrospectively on who got treated with what and say, “Well it looks like the patients who got the more aggressive regimen other than R-CHOP did better,” but they don’t really tell us what these patients should be treated with. Approximately 70% of patients with double-hit lymphoma tend to survive, and again, they really do not have viable treatment options. They just go through one therapy after another and you don’t have anything [new] to offer them.

Could you discuss the compound CPI-613?

That is where this trial comes in. It’s a novel agent and essentially what [researchers] were looking at was energy metabolism—directed cancer therapy. We know that some of the malignantly transformed [cells] use a lot of energy. Therefore, they looked at the building blocks inside of the Krebs cycle and there are a couple of enzymes and they can block with an analog. It’s an analog of lipoic acid, so it is covalently bound to the mitochondrial tricarboxylic acid cycle. The two enzymes directly involved in this particular compound are pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. By blocking the mitochondrial energy metabolism, this leads to apoptosis that occurs in the autophagy; the cells basically run out of energy.

After looking at this, they studied many preclinical models in different kinds of cancer types. They also looked at a couple cell lines that capitulated Burkitt lymphoma and they were able to demonstrate that they could make the cell more sensitive to the compound if they increased the level of c-Myc expression inside the cell. That is the proof of principle.

The compound was studied in a few phase I trials and in one of the studies, there was 1 patient who had Burkitt lymphoma that had been refractory to 2 prior chemotherapies, full allogenic transplant, and after all of that, they gave her this compound, CPI-613. After 17 cycles, she remained in partial remission at 1 year of therapy. They ended up resecting that mass and she was in remission for about 3 years.

How many patients are you looking to enroll on this phase II study?

There are 17 patients in each arm; there is 1 arm specifically for Burkitt lymphoma and there is one arm specifically for the non—Burkitt subtypes. We do that because we are not sure biologically what will happen and, in theory, in may be true that the patients with Burkitt lymphoma have more sensitive disease than the patients with non-Burkitt lymphoma because of this additional BCL2 issue. If BCL2 is a problem, we don’t want to “throw out the baby with the bathwater” on the Burkitt arm.

What is the design of the study?

It is a pretty straightforward study design. Patients are getting an induction treatment [of CPI-613 in the format of] 2-hour infusions for 5 days and that cycle repeats after 14 days. After 2 treatments like that, they get a cycle of maintenance and the only difference is it is a 3-week cycle, after which there is a treatment assessment in terms of efficacy. We are looking for ORR as the primary endpoint, but obviously we are interested in duration of response, progression- free survival, overall survival, and we are going to take a look at toxicities. Also, some of these patients [may] have heavy bone marrow involvement [from the treatment]. We are also going to look to see if there are any pretreatment biomarkers that predict outcome.

The study is open at City of Hope, and we are working on some other sites. Ideally, we wanted to accrue 10 patients per year and we wanted 1-year of follow-up for the data analysis.

What additional questions do you want to answer once this trial is complete?

It is important for physicians and patients to know that they can use this as a bridge. We don’t necessarily think that a single agent is going to cure someone, but if they can get this treatment and then go on to autologous or allogeneic transplant, if appropriate, then they have a new treatment option that could be curative. That is really important. I don’t want people to think they have to do this and they can’t do anything else.

CPI-613: A First-in-Class Therapeutic Agent Targeting Cancer Cell Metabolism. Rafael Pharmaceuticals. https://bit.ly/2Xw20Sh. Accessed July 8, 2019.