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SOHO 2021 | Ulocuplumab & ibrutinib for CXCR4-mutated Waldenström’s macroglobulinemia

Jorge Castillo, MD, of the Dana-Farber Cancer Institute, Boston, MA, talks on the results of a Phase I trial (NCT03225716) investigating the efficacy of the CXCR4 antagonist ulocuplumab in combination with the BTK inhibitor ibrutinib for patients with CXCR4-mutated Waldenström’s macroglobulinemia. Dr Castillo describes the rationale for the trial and reports that the study, which enrolled 12 patients, yielded a 100% response rate. A study investigating mavorixafor, a small molecule targeting CXCR4, in combination with ibrutinib is also underway in patients with CXCR4-mutated Waldenström’s macroglobulinemia. This interview took place during the ninth annual meeting of the Society of Hematologic Oncology (SOHO 2021) congress.

Transcript (edited for clarity)

The study that combined the BTK inhibitor, ibrutinib and the anti-CXCR4 monocular antibody ulocuplumab was actually the first genomically driven clinical trial in patients with Waldenström’s. I think that is why it is such an important study, but not only that, it also helped us understand what is the role of CXCR4 as a target in patients with Waldenström’s. We had a number of pre-clinical data, laboratory data suggesting that patients with CXCR4 mutations or at least cells that had CXCR4 mutations were more resistant to BTK inhibitors...

The study that combined the BTK inhibitor, ibrutinib and the anti-CXCR4 monocular antibody ulocuplumab was actually the first genomically driven clinical trial in patients with Waldenström’s. I think that is why it is such an important study, but not only that, it also helped us understand what is the role of CXCR4 as a target in patients with Waldenström’s. We had a number of pre-clinical data, laboratory data suggesting that patients with CXCR4 mutations or at least cells that had CXCR4 mutations were more resistant to BTK inhibitors. When we evaluated the data from the phase two in patients with relapse disease, as well as the phase two in patient with frontline disease, and then retrospectively we really realized that patients with CXCR4 mutations tend to have lower responses. They tend to have more superficial responses, and then also the duration of that response is actually shorter.

That really was the impetus for us to try to look for a way to target CXCR4, in addition to BTK. This is where this ibrutinib or ulocuplumab came around. Ulocuplumab was initially tried in myeloma. I don’t think it really did what company wanted it to do. When we were trying to get ulocuplumab for our clinical trial, they agreed on covering the study initially, but then they made the decision, the company made the decision on not continuing the clinical developments of these agents. Therefore, they gave us about enough to run for 12 patients, kind of a proof of concept type of study and that’s exactly what we did. We enrolled 12 patients on this study, all the patients had CXCR4 mutations and they were exposed to ibrutinib by a standard dose of 420mg by mouth once daily indefinitely and ulocuplumab was given intravenously.

It’s actually very easy to give and the antibody compared to our experiences with rituximab, for example. These were one hour infusions, really no infusion reactions that I can speak of, which is unusual for other antibodies in patients with Waldenström’s. It was weekly infusions for the first 4 weeks and then for the first 8 weeks and then every other week for 4 additional months for six months duration and that was the end of it. Ibrutinib continued indefinitely. Most of the patients actually responded to the treatment. We have a response rate, it was 100% with a major response rate that was very, very impressive, at least in the 70 to 80% range. The time to response was faster too, than what we expected. The time to response on ibrutinib is typically anywhere between 3 and 6 months, with this agent it was about anywhere between 2 and 3 months and it was actually definitely faster responses, deeper responses that we saw in this.

The company will probably not continue the commercialization of ulocuplumab. I think this study really tells us that it was a proof of concept that CXCR4, it is a target and that we can target it. Now we can go beyond that and say, do we need or can we give this type of anti-CXCR4 agents, for patients who have CXCR4 mutations only, which is what happens in Waldenström’s. There’s a number of malignancies that have CXCR4 overexpression, so can it be possible that if we modulate CXCR4 with antibodies or other agents, can we have benefit on these malignancies that also have CXCR4 overexpression?

So thinking about that, we are now running another clinical trial specifically for patients with CXCR4 mutations in Waldenström’s, combining ibrutinib with a small molecule targeting CXCR4, it’s called [inaudible 00:04:02], so that study is a multicenter study. There are centers open in Europe and the United States. I think the phase one, two study is aiming to accrue 18 patients. I think we are very much past half of the accrual at this time. I think some of this data will be presented later this year at ASH, if I’m not mistaken, so you will be seeing some of that. We are very excited on exploiting CXCR4 as a potential target in patients Waldenström’s.

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Disclosures

Jorge Castillo receives research funds and/or honoraria from Abbvie, Beigene, Janssen, Pharmacyclics, Roche, TG Therapeutics.