ASH 2021 | GO plus midostaurin and intensive chemotherapy in CBF and FLT-mut AML
Evidence has demonstrated that the addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy improves efficacy in patients with FLT3-mutated acute myeloid leukemia (AML). This finding provided the rationale for investigating the addition of GO to midostaurin and intensive chemotherapy, the current standard of care treatment option in FLT3-mutated AML. Additionally, core-binding factor (CBF) AML has been shown to respond well to tyrosine kinase KIT inhibition and thus, adding midostaurin to the standard combination of GO plus intensive chemotherapy seems promising. Christoph Röllig, MD, MSc, Dresden University of Technology, Dresden, Germany, shares the findings of the Phase I MODULE trial (NCT04385290) investigating the feasibility of combining midostaurin plus GO and intensive chemotherapy in patients with FLT3-mutated AML or CBF AML. The dose-escalation study identified that two doses of GO can be safely combined with a standard dose of midostaurin in the context of standard induction. The combination was shown to be safe and feasible and will be further investigated in the randomized Phase II MAGNOLIA and MAGMA studies in CBF and FLT-mutated AML, respectively. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.
Transcript (edited for clarity)
We explored the feasibility to combine two targeted novel agents, gemtuzumab ozogamicin and midostaurin in combination with standard induction chemotherapy, newly diagnosed AMLs. And there are two main reasons why it may be a good idea to combine these two agents. First, most AMLs express CD33, including FLT3-mutated AMLs. And in this subgroup, gemtuzumab ozogamicin seems to be particularly efficacious...
We explored the feasibility to combine two targeted novel agents, gemtuzumab ozogamicin and midostaurin in combination with standard induction chemotherapy, newly diagnosed AMLs. And there are two main reasons why it may be a good idea to combine these two agents. First, most AMLs express CD33, including FLT3-mutated AMLs. And in this subgroup, gemtuzumab ozogamicin seems to be particularly efficacious. Second, a KIT inhibition by midostaurin seems to be beneficial in CBF-AML, since KIT is often overexpressed or mutated in CBF-AML. Therefore, in FLT3-mutated AML or CBF-AML using both gemtuzumab ozogamicin and midostaurin in addition to standard treatment seems to be a good idea, and so far we don’t have any prospective evidence that it is actually feasible to combine all these drugs.
And for this purpose, we designed a trial named MOSAIC, and this MOSAIC trial combines a Phase I part named MODULE with two consecutive randomized Phase II parts called MAGNOLIA for CBF-AML, and MAGMA for FLT3-mutated AML. And we report at this ASH meeting the results of the completed Phase I part, which is named MODULE. In order to find out whether it’s feasible or which combination or which dose combination is best suited for combining these two novel agents with standard induction chemotherapy, we had dose level one with two doses of GO plus half the standard dose of midostaurin; dose level two with two doses of GO plus full dose midostaurin, 50 mg BID; and dose level three with three doses of GO plus full dose of midostaurin and 50 mg BID.
And when we did this Phase I trial, it turned out that the dose level two was defined as safe. And therefore we did not progress to dose level three since we saw DLTs, dose-limiting toxicity, in the dose level two. Therefore, we can conclude, based on the results of this trial, that two doses of gemtuzumab ozogamicin can be safely combined with a standard dose of midostaurin in the context of standard intensive induction treatment. We are currently treating patients with this combination in the randomized MAGNOLIA trial and in the randomized MAGMA trial in CBF-AML or FLT3-mutated AML respectively.
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