Results of a Phase I Open-Label Study of Decitabine in Combination with Midostaurin (PKC412) for Elderly (Age ≥ 60) Newly Diagnosed or Relapsed/Refractory Adult Patients with Acute Myeloid Leukemia,

We present data from a phase I, single-center study designed to determine the MTD and recommended Phase II dose of midostaurin (PKC412), a FLT3 inhibitor, combined either sequentially (days 8–21) or concurrently (days 1–28) with decitabine 20 mg/m2 days 1–5 in AML patients. Additional endpoints: tolerability; exploratory activity assessments. Adult AML patients with relapsed or refractory (R/R) disease or elderly (≥ 60 years) patients unable to receive standard induction chemotherapy, with ECOG PS ≤2, were eligible and received treatment for 3 cycles or until disease progression. Previous hypomethylating agents were allowed.

Enrollment is complete with 16 patients (Table 1) with 15 evaluable for safety (1 pt withdrew prior to receiving any midostaurin). One patient in cohort 1 remains on study in cycle 14. Median number of cycles completed was 2 with 5 patients receiving 3 or more cycles. Median age was 68 years (range 48–81) with 9 males. The number of newly diagnosed and R/R patients was evenly split at 8 each. Of note, 3 of 8 patients (38%) with R/R disease had relapsed subsequent to allogeneic hematopoietic stem cell transplant (HSCT). Only 2 of 16 patients (13%) had FLT3 ITD mutations and no patient had KIT mutations. Additionally, 44% of patients had received prior therapy with either azacitidine or decitabine.

All patients whom received treatment (15) experienced adverse events (AE), the majority of which were Grade 1/2 in severity and included fatigue, nausea, mouth sores, and insomnia. Most AEs were hematologic, including anemia, thrombocytopenia, and neutropenia as expected in this population. Three patients developed dose limiting toxicities: 2 patients in cohort 3 developed pulmonary edema requiring mechanical ventilation and 1 patient in cohort 2 developed a prolonged QTc > 500 msec. All but two of 15 patients required admission for neutropenic fever. Three patients developed fungal (2) or viral pneumonia (1) and expired. However, most study treatments were given in the clinic allowing patients to spend a majority of the time as an outpatient.

Of twelve patients evaluable for response, 10 (83%) achieved stable disease (SD) or better while on trial. Three of the 12 patients (25%) had a complete response (CR or CRi) after 1 cycle (28 days) and 2 of these patients were able to undergo allogeneic HSCT. Of the two patients with FLT3 ITD mutations, one patient was evaluable for response and achieved a CR (cohort 2). Pharmacokinetic analysis is ongoing.

These data indicate that the combination of decitabine with sequential midostaurin is possible without significant unexpected toxicity. The MTD for this combination was determined to be decitabine 20mg/m² IV daily × 5 days (days 1–5) followed by midostaurin 50mg po bid days 8–21 given every 4 weeks. In addition, the combination shows promising clinical activity in R/R and untreated AML in elderly patients.

No relevant conflicts of interest to declare.