A phase 1 study on midostaurin plus panobinostat in unfit acute myeloid leukemia and high-risk myelodysplastic syndrome

Introduction: Midostaurin is a non-specific FLT3 inhibitor that showed anti-leukemic activity against both FLT3 mutated as well as unmutated Acute Myeloid Leukemia (AML) in early phase studies. Panobinostat, a potent oral pan-acetylase inhibitor had also shown significant anti-leukemic signals in early phase studies. In the preclinical study, our group had previously reported synergistic anti-leukemic activity when an FLT3 inhibitor was used in combination with an HDAC inhibitor in vitro as well as in vivo animal study. The current study is our first bench-to-bedside study to further evaluate this combination therapy in AML patients. Method: Elderly AML who were either newly diagnosed and declined Hypomethylating Agent (HMA) or who failed HMA, MDS-RAEB-2, and relapsed refractory AML who were unfit for intensive chemotherapy or have no other treatment option were eligible regardless of FLT3 mutation status. The classical 3+3 dose escalation method was applied. Dose level 1 for Midostaurin was 50 mg bd and Panobinostat was 10 mg 3 times per week. Dose escalations were planned with only one drug escalation at a time on every level. Midostaurin was administered daily as a continuous cycle while Panobinostat was given for the first 3 weeks of a 4 weeks cycle. Dose-limiting toxicities were defined as grade 3 or more non-haematologic toxicities occurring within the first cycle. Chronic toxicity is defined as recurrent or persistent adverse events that are possibly related to investigational products. Response assessments were done at post cycle 2 and cycle 4. Concomitant treatment with hydroxyurea was allowed up to cycle 1 day 14 to control leukocytosis if needed. Results: A total of 7 patients have been recruited with a median age of 71 years old (range: 47 to 82 years). 2 patients had MDS-RAEB2, one with Acute myelomonocytic leukemia, 3 had AML with myelodysplasia-related changes (AML-MRC) and one with de novo FLT3-ITD AML. One of the AML-MRC had FLT3-ITD mutation and another had FLT3-TKD mutation. 4 out of 7 had prior HMA therapy, the remaining three were treatment naive. 2 patients were not evaluable for DLT and response assessment due to progressive disease during cycle 1. 2 completed 2 cycles, the other 3 completed 4, 5 and 9 cycles respectively. No DLT was observed within cycle 1. Significant grade 1-2 treatment emerging adverse events were anorexia (4/5), fatigue (3/5), nausea (2/5), and dysgeusia (2/5). These toxicities persist beyond cycle 1 with increasing frequency. Grade 2 fatigue was observed in 4 patients, grade 2 anorexia in 4 patients, grade 1 dysgeusia in 4 patients, and grade 3 lipase elevation in one patient. 4 out of 5 patients developed severe grade 4 thrombocytopenia requiring regular platelet transfusion. Two had baseline grade 4 thrombocytopenia but the severity worsen after 1 cycle of treatment. These were thought to be chronic toxicities because the symptoms were largely resolved or improved during dose interruptions. In view of significant chronic toxicities, no further dose escalation was done and dose level 1 would be further evaluated in the expansion cohort. 5 out 7 had post cycle 2 response assessment. One patient with FLT3-TKD achieved CRi, one AML-MRC showed 50% blast reduction, and the remaining 3 had stable disease. The one who achieved CRi eventually withdrew from the study after completing 6 cycles due to fatigue, anorexia, severe grade 4 thrombocytopenia with gastrointestinal bleeding. His transfusion requirement has also reduced. He remained in stable disease without further anti-leukemic therapy until February 2019 (16 months after withdrawal from the study) when he suffered a frank relapse. One with stable disease who demised during cycle 10 due to complicated acute cholecystitis and sepsis. The remaining 5 demised due to progressive disease. Conclusion: Even though no DLT was observed within cycle 1, significant chronic toxicities such as fatigue and anorexia were observed. The limited anti-leukemic activity was observed in 5 evaluable patients. Further exploration with different dosing schedules or used in combination with other anti-leukemic agents is required to improve the tolerability profile and efficacy.