Gilteritinib as an adjunct to standard therapy (venetoclax + azacitidine) in patients with newly diagnosed acute myeloid leukemia who cannot tolerate intensive chemotherapy

Acute leukemias are rapidly progressing, aggressive forms of cancer that arise from immature white blood cells or bone marrow cells and usually spread very quickly. The malignant leukemia cells develop in the bone marrow and displace the healthy bone marrow, preventing the production of sufficient numbers of functional blood cells. Typical symptoms include frequent infections, bleeding, decreased energy, and shortness of breath. In younger patients, intensive chemotherapy is often used, which can achieve complete remission in many cases. For older patients with AML or for patients who are not suitable for intensive chemotherapy, the effective combination therapy of venetoclax and azacitidine has already been approved as an alternative.

Azacitidine is a chemotherapeutic agent that directly attacks the leukemia cells. Venetoclax is a so-called BCL-2 inhibitor that additionally triggers the natural death of cancer cells. The combination of the two drugs targets leukemia cells more precisely while sparing healthy cells. Compared to intensive chemotherapy, it is better tolerated due to its targeted action and fewer acute side effects. The FLT3 mutation is one of the most common genetic alterations in AML and has important prognostic and therapeutic significance. The mutation affects a specific protein (tyrosine kinase) that promotes the growth and proliferation of cancer cells. The study drug, gilteritinib, is a so-called tyrosine kinase inhibitor (TKI) designed to block this protein. The drug is already approved in Germany as a monotherapy for the treatment of relapsed or refractory AML.

The goal of this Phase 2 study is to determine the best-tolerated and most effective dose of gilteritinib in combination with the standard treatment of venetoclax and azacitidine.

As part of the study, patients will be randomly assigned to one of four groups, all of which will receive all three medications in 28-day cycles. Group 1 will receive gilteritinib on days 1–28, as well as venetoclax and azacitidine on days 1–7. Group 2 receives gilteritinib on days 8–28 and venetoclax and azacitidine on days 1–7. Group 3 receives gilteritinib on days 1–28, venetoclax on days 1–14, and azacitidine on days 1–7. Group 4 receives gilteritinib on days 8–28, venetoclax on days 1–14, and azacitidine on days 1–7. The study is open-label, meaning that medical staff and patients know which medications are being administered at each time point. The primary endpoint of the study is the ratio of actual drug doses administered to the originally planned doses. Women and men aged 18 and older with newly diagnosed AML and an FLT3 mutation who are not eligible for standard induction chemotherapy and have received no more than one cycle of venetoclax plus azacitidine may participate in this study.