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Single Institution Phase 1 Study on Combination Therapy of Midostaurin and Panobinostat in Acute Myeloid Leukemia - the Interim Report

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Background: Midostaurin is a non-specific FLT3 inhibitor which showed anti-leukemic activity against both FLT3 mutated as well as unmutated acute myeloid leukemia (AML) in early phase studies. Panobinostat, a potent… Click to show full abstract

Background: Midostaurin is a non-specific FLT3 inhibitor which showed anti-leukemic activity against both FLT3 mutated as well as unmutated acute myeloid leukemia (AML) in early phase studies. Panobinostat, a potent oral pandeacetylase inhibitor had also showed significant anti-leukemic signal in early phase studies. In the pre-clinical study, our group had previously reported synergistic anti-leukemic activity when a FLT3 inhibitor was used in combination with a 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 decline 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 50mg bd and Panobinostat was 10mg 3 times per week. Dose escalations were planned with only one drug escalation at a time on every level. Midostaurin was administered daily as 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 7 patients have been recruited with a median age of 71 years old (range: 47 to 82). 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 naïve. 2 patients were not evaluable for DLT and response assessment due to progressive disease. 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 were 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 evaluated further in 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 study after completing 6 cycles due to fatigue, anorexia, severe grade 4 thrombocytopenia with gastrointestinal bleeding. As of report date, he remains alive and well after 9 months off study. His transfusion requirement has also reduced. One succumbed to intracranial bleeding during his cycle 10. He was in stable disease. 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. Objective anti-leukemic activity was observed in 5 evaluable patients. Further expansion cohort would provide a clearer picture on the anti-leukemic effect as well as the chronic toxicities. Chng: Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Merck: Research Funding; Aslan: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding.

Keywords: anti leukemic; study; flt3; cycle; leukemia; midostaurin

Journal Title: Blood
Year Published: 2018

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