Pevonedistat plus belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome: A phase I multicenter study.

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e19015 Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy, with particularly dismal prognosis in the relapsed or refractory (R/R) setting, with a median overall survival of approximately 6 months. There has been increasing interest in novel therapeutic approaches to intelligently harness cellular pathways to improve outcomes in this difficult to treat population. Pevonedistat, a first-in-class NEDD8 inhibitor, and Belinostat a HDAC inhibitor work synergistically in AML cells and human xenograft AML models supporting the clinical rationale for this Phase I study. Methods: A Phase I dose-escalation study with a 3+3 design was performed to assess safety and tolerability of pevonedistat plus belinostat. Beliniostat (D1-5) and Pevonedistat(D1,3,5) were administered in a 21 day cycle until disease progression or unacceptable toxicity. Primary endpoint was identification of MTD/RP2D, secondary endpoints included toxicity, efficacy, pharmacokinetic interactions, and pharmacodynamic studies. Results: 18 patients (67% female; median age 67.5 (41-74)), 16 of whom had AML, were treated at 5 dose levels (belinostat 800-1000mg/m2, pevonedistat 20-50mg/m2), no dose limiting toxicities were noted. Average number of prior lines of therapy was 3. Most Grade 3 or 4 toxicities were hematologic (Table). Maximum number of cycles reached was 8. Best response was stable disease in four patients, and CR in one patient. The remainder had progressive disease or were not evaluable. Most common reason for discontinuation was disease progression (67%), 11% treatment ended per protocol criteria, 6% pursued alternative therapy, 6% due to side effects. The patient achieving CR was a 54 year old female with BRAF and TET2 mutation, primarily refractory to 7+3 and also unresponsive to second line azacitidine and venetoclax. After CR, she received an allogeneic stem cell transplant and remains in remission with 2 years of follow up. Conclusions: The combination of pevonedistat plus belinostat is safe in adult R/R AML with a manageable, primarily hematologic profile, and modest but notable activity in this heavily treated population. This regimen may be effective as a bridge to transplant in some patients. MTD was not reached in this study. Clinical trial information: NCT03772925 . [Table: see text]