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EHA 2021 | BGB-11417-101: first-in-human trial of BGB-1147 for R/R B-cell malignancies

Chan Yoon Cheah, MBBS, Linear Clinical Research and Sir Charles Gairdner Hospital, Perth, Australia, outlines the preliminary safety data from the first-in-human Phase I/Ib BGB-11417-101 study (NCT04277637) investigating the safety, tolerability, maximum tolerated dose and Phase II dose of BGB-11417 in patients with relapse/refractory (R/R) B-cell malignancies. BGB-11417 is a highly selective and potent BCL-2 inhibitor which has demonstrated efficacy in patients with acute lymphoblastic leukemia (ALL) and mantle cell lymphoma (MCL), as well as in diffuse large B-cell lymphoma (DLBCL) xenograft models. Dr Cheah reports on early Phase I results, which have shown that BGB-11417 is well-tolerated. Thus far, nine patients have been treated in the trial, including seven patients with lymphoma and two patients with chronic lymphocytic leukemia (CLL). This interview took place at the virtual European Hematology Association (EHA) Congress 2021.

Transcript (edited for clarity)

BGB-11417 is a Phase I/Ib dose escalation trial of the BCL2 inhibitor. It’s pretty selective and has a greater than 2000-fold selectivity for BCL2, versus other BCL family proteins, such as BCL-XL, MCL1, BCL2A1. It is also about 10-fold more potent than the first-in-class agent venetoclax. So, the study is a parallel dose escalation design in B-cell malignancies, with cohorts in both lymphoma and chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström’s macroglobulinemia, with the potential to later do combinations with zanubrutinib, which is Beigene’s BTK inhibitor...

BGB-11417 is a Phase I/Ib dose escalation trial of the BCL2 inhibitor. It’s pretty selective and has a greater than 2000-fold selectivity for BCL2, versus other BCL family proteins, such as BCL-XL, MCL1, BCL2A1. It is also about 10-fold more potent than the first-in-class agent venetoclax. So, the study is a parallel dose escalation design in B-cell malignancies, with cohorts in both lymphoma and chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström’s macroglobulinemia, with the potential to later do combinations with zanubrutinib, which is Beigene’s BTK inhibitor.

The purpose of Phase I and Ib of the study is to determine the safety profile, and recommended Phase II dose. Much like in venetoclax, there is a ramp up in terms of dosing, to avoid the risk of tumor lysis syndrome, which is a known class toxicity of BCL2 inhibitors, such as venetoclax, and a similar dose escalation schedule has been employed in this study. I guess the difference is that in non-Hodgkin lymphoma, particularly in non-mantle cell subtypes, where we know from the venetoclax experience that the risk of tumor lysis syndrome doesn’t appear to be as great, there’s a pretty quick two-day ramp-up, whereas in CLL and other high-risk malignancies, the ramp-up occurs over eight weeks.

We’ve treated nine patients at the data cut-off, which is toward the end of March this year. Seven patients with lymphoma, and two patients with CLL, and the drug has been pretty well tolerated, actually. It’s been the adverse events, as you can see, if you look at the abstract and the poster, are pretty mild. The majority have been grade one or two with a couple of grade three adverse events, being neutropenia, and a couple of patients with ALT abnormalities.

The efficacy so far, it’s pretty early days in terms of efficacy. We’ve seen a little bit of biochemical tumor lysis in a patient with CLL, but other than that, not too much in terms of safety signals, it’s been well tolerated. We have had, among the lymphoma patients n equals seven, we’ve had quite a few patients remain stable, including patients with pretty aggressive large-cell lymphoma have had fairly durable, stable disease. So, not quite a response, but among the patients with CLL, we’ve certainly seen some reductions in lymphocyte count, even at lower doses. And so, we’re pretty confident that this is going to be an active agent in, in B-cell malignancies.

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