ASH 2024 | A Phase I study of CLAG-M and lintuzumab-Ac225 in high-risk R/R AML

So for the first abstract or presentation, we reported outcomes in high-risk patients who were treated on our phase one study of CLAG-M, which is salvage chemotherapy, administered along with lintuzumab-Ac225, which is a radio-labeled antibody against CD33. So this is a phase one study that was conducted between 2019 and 2022. And during this period, we enrolled and treated 26 patients with CLAG-M, which is cladribine, cytarabine, and mitoxantrone. And then afterwards, lintuzumab-Ac225, which is a radiolabeled antibody against CD33. During the period of enrollment, we enrolled patients particularly with two high-risk features. One, patients with either poor cytogenetics or a P53 mutation. And so specifically, poor disease, we enrolled, I think, about half of patients with that. But secondly, we also enrolled a fair proportion of patients who prior to treatment on this study received a venetoclax-based combination. All of them had received VEN-HMA, either venetoclax with azacitidine or decitabine. And this is an emerging sort of difficult-to-treat population in AML. There have been recent studies that indicate with subsequent therapy, very few patients can respond between 20 and 30 percent, achieve a response with a subsequent therapy after failure of VEN-HMA. And survival overall is very poor in the range of about three to four months. So a critical need is this population. So for this presentation, we identified 13 patients who were treated previously prior to CLAG-M lintuzumab with VEN-HMA. Of these patients, we found the majority of these patients had mutated TP53, which is unsurprising because overall that represents sort of a significant resistant or refractory population amongst AML patients in general. So with these 13 patients the majority of these patients were treated at what we determined to be the maximum tolerated dose and the recommended phase 2 dose which is 0.75 microcurie per kilogram so of these 13 patients four were treated at that dose and then the second half so a significant proportion otherwise was treated at 0.5 microcurie per kilogram which is the dose below a recommended at phase 2 dose. Again, of these 13 patients that were treated with venetoclax previously, 9 had a P53 mutation, 10 overall had adverse risk AML by ELN 2022 criteria. And then just in terms of the breakdown, there were two patients who received CLAG-M lintuzumab after frontline venetoclax and another three patients who received CLAG-M lintuzumab as third-line therapy. So after some therapy and then VEN-HMA, and then another eight patients who received this treatment beyond the third line. That was the breakdown of patients who received this treatment. What we found were patients who received CLAG-M lintuzumab after VEN-HMA frontline therapy. Actually, all patients, those two patients both responded and both had MRD negative responses. Of the three patients who received VEN-HMA as a second line or as a first salvage therapy, two out of these three patients are 67% responded. Both of these patients were MRD negative by flow. And then finally, of the patients who had received this as subsequent line therapy, so either fourth line or beyond, we still saw a modest response rate. Three patients responded for a response rate around 37.5%. Overall, for this difficult to treat population, we saw an encouraging survival. So if given this therapy, median survival overall was 7.3 months. In patients who had either received venetoclax HMA as frontline therapy or first salvage, the median survival actually was not reached at two years. And so this is a pretty effective salvage as either first or second salvage after venetoclax-based therapy. Finally, amongst TP53 mutated patients, of which there were nine, we saw responses in five patients, or 56%. If they achieved a CR, these were all MRD negative CRs. Overall, their survival was modestly improved compared to historic outcomes at around seven months. The overall message with this abstract is that really the hardest to treat patients with relapsed or refractory AML now are those patients who fail VEN-HMA and particularly those patients with P53 mutations. When we looked at these difficult to treat patients or these patients for which there’s the high need for salvage, we saw pretty encouraging outcomes, particularly the fact that half of these patients with P53 mutations were able to respond, survival beyond what we kind of historically see around three or four months as well. All in all, sort of supporting that this combination should be further investigated in a definitive fashion in either a phase two or phase three study.

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