Combination of Midostaurin and Gemtuzumab Ozogamicin as Standard First-Line Therapy for Acute Myeloid Leukemia (MOSAIC)

Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system characterized by the uncontrolled proliferation of myeloid blasts (immature white blood cells) in the bone marrow and blood. Young patients (under 75 years of age) without serious comorbidities and in good general health should receive intensive chemotherapy as standard treatment. With this intensive treatment, complete remission can be achieved in many cases, meaning that no cancer cells are detectable. An important prognostic factor for treatment is the type of mutation detected in the disease. A mutation in the CBF gene is associated with a more favorable prognosis and a higher rate of complete remission. However, mutations or overexpression of so-called receptor tyrosine kinases (RTKs)—proteins on the cell surface—are associated with a higher risk of disease recurrence. Among others, the FLT3 gene may be affected in these cases. The already approved drug midostaurin inhibits these tyrosine kinases and is already approved for the treatment of AML in combination with chemotherapy.

The already approved drug gemtuzumab ozogamicin represents another treatment option (as monotherapy or in combination with chemotherapy). Gemtuzumab ozogamicin is an antibody-drug conjugate that specifically binds to the CD33 protein on cancer cells and releases the toxic agent inside the cancer cells. The CD33 protein is very commonly detected in AML with CBF and FLT3 mutations. However, insufficient data have been collected to date on the combination of midostaurin and gemtuzumab ozogamicin.

The objective of this Phase 1/2 study is to investigate the efficacy of the combination therapy consisting of midostaurin, gemtuzumab ozogamicin, and standard chemotherapy. The study is divided into two phases. In Phase 1, the optimal and maximum tolerable dose of the combination therapy midostaurin + gemtuzumab ozogamicin will be determined. To this end, patient groups will be formed to receive midostaurin + gemtuzumab ozogamicin at different dose levels. The treatment will also be combined with standard chemotherapy (cytarabine + daunorubicin).

Phase 2 of the study aims to evaluate the efficacy of adding midostaurin or gemtuzumab ozogamicin. Patients with the CBF mutation will be randomly assigned to two groups. In Study Arm 1, patients will receive the dose of midostaurin and gemtuzumab ozogamicin determined in Phase 1 in combination with standard chemotherapy (cytarabine + daunorubicin). Control arm 1 will receive standard chemotherapy (cytarabine + daunorubicin) and gemtuzumab ozogamicin (without midostaurin).

Patients with an FLT3 mutation are also randomly assigned to two groups. In Study Arm 2, patients receive the dose of midostaurin and gemtuzumab ozogamicin determined in Phase 1 in combination with standard chemotherapy (cytarabine + daunorubicin). Control arm 2 receives standard chemotherapy (cytarabine + daunorubicin) and midostaurin (without gemtuzumab ozogamicin).

The study is open-label, meaning that both the medical staff and the patients know which medications are being administered. Treatments and follow-up examinations as part of the study will continue for up to 3 years, during which the efficacy of the therapy and the occurrence of side effects from the various medications will be evaluated.

Women and men between the ages of 18 and 75 with untreated AML and a FLT3 or CBF mutation are eligible to participate in this study.