Prospective randomized multicenter phase III trial of decitabine and Venetoclax administered in combination with all-trans retinoic acid or placebo in patients with acute myeloid leukemia who are ineligible for induction chemotherapy

• Applicant: Professor Dr. Michael Lübbert, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 367848349

Acute myeloid leukemia (AML) is a type of cancer that occurs predominantly in the elderly, with age of diagnosis often 70+ years. Until recently, therapeutic options for these patients were very limited, since intensive chemotherapy, standard for younger AML patients, often led to unacceptable toxicities, and frequently was not as effective as in younger patients. Better tolerated, mild AML therapy is provided by the epigenetically active medicines Decitabine and Azacitidine. These very closely related drugs are given on an outpatient basis, are well tolerated also by elderly patients with comorbidities, and thought to act by reprogramming of the leukemia cells, thus probably by different mechanisms of action than conventional chemotherapy. To enhance the efficacy of this epigenetic therapy - by itself not leading to cure of AML - numerous drug combinations have been clinically tested during the last years. Through a collaboration within a trial network of physicians from different German University Hospitals, we could demonstrate in the multicenter clinical trial DECIDER (registered under NCT00867672) that Decitabine infusions in combination with a vitamin A derivative (ATRA capsules) led to an increase in overall survival of elderly AML patients (median age 76 years) compared to treatment with Decitabine alone. Within the planned successor study (DECIDER-2) our primary objective is to confirm the extension of patient survival with ATRA add-on compared to treatment without ATRA add-on. Half of the patients will receive ATRA capsules in addition to Decitabine, the other half will receive placebo capsules instead of ATRA in combination with Decitabine (double-blind randomized study). All patients will receive, in addition, a third drug (Venetoclax capsules) with the aim to accelerate the programmed cell death in the AML cells. The study is planned to accrue 250 patients at more than 30 German study sites. While the most important study question is to find out whether patients receiving ATRA will live longer than patients receiving placebo (in combination with the other two drugs), a second important objective is the measurement of quality of life before and during this AML therapy. Here we hope that patients benefiting from the treatment will also enjoy an improvement of their quality of life. In accompanying laboratory studies, the mechanism of action of this novel therapy shall be studied using bone marrow and blood cells of the patients, in order to be able to make better predictions about which patient will profit most from such chemotherapy-free treatment.

• DFG Programme: Clinical Trials
• Co-Investigator: Professor Dr. Ralph Wäsch