Phase I/II Study of Combination of Sorafenib, Vorinostat, and Bortezomib in Acute Myeloid Leukemia with FLT3-ITD Mutation or Monosomy 5, 7, or Complex Cytogenetics

Introduction

We report the phase I data from ongoing phase I/II study of combination of targeted agents sorafenib, vorinostat and bortezomib in poor-risk AML. Our findings from a previous phase I study, performed at Indiana University, of the combination of sorafenib and vorinostat in patients with AML suggested that two major groups of patients may benefit most from this targeted regimen, patients with FLT3-ITD mutation, and those with complex or poor-risk cytogenetics (monosomy 5 or 7). In addition, our findings were suggestive of a synergistic action obtained by inhibition of p52NFKB, a down-stream target of proteosome inhibition. With the hypothesis that addition of proteasome inhibitor bortezomib would be of benefit towards such synergism, a phase I/II clinical trial combining bortezomib with sorafenib and vorinostat was initiated. The phase I data is reported here.

Methods

The phase I portion of the trial utilized a traditional 3+3 design on five cohorts to determine the MTD of the combination. Eligibility required age ≥18, a confirmed baseline diagnosis of AML by the revised guidelines of the International Working Group for AML, and included untreated disease in elderly or relapsed/refractory disease in all ages, monosomy 5,7 or complex cytogenetics or positive FLT3-ITD mutation, ECOG PS 0-2, and adequate kidney and liver function. Dose limiting non-hematologic toxicity was defined per the CTCAE v4.0 criteria. Hematologic toxicity was prolonged cytopenia with <5% cellularity and no evidence of leukemia in the bone marrow lasting >42 days after discontinuation of therapy. The treatment was given in cycles, with each cycle consisting of 2 weeks treatment followed by 1 week off. Dose and/or administration schedule of drugs were escalated between the cohorts.

Results

Seventeen patients were enrolled on the phase I portion. Fifteen patients completed at least one cycle of treatment and 2 were taken off earlier due to disease progression. The median age was 51 years (24-73), and 10 (59%) patients were male. Sixteen patients had prior therapy at time of enrollment and 59% were heavily pretreated (≥3 lines of therapy) including stem cell transplantation in 29%. Fifty nine percent had FLT3-ITD mutation and 53% had poor-risk cytogenetics. No DLTs were seen in all 5 cohorts and MTD was not reached. The safe dose for phase II was determined at sorafenib 400 mg bid, vorinostat 200 mg bid (both for 14 days), and bortezomib 1.3 mg/m²IV on days 1,4,8,11, every 21 days. Most common grade 1-2 toxicities were diarrhea (59%), nausea (41%), vomiting (24%) and rash (18%). Majority of toxicities were grade 1. Response was observed in 6 patients (40%) with 4 achieving a complete remission (27%). All responders had relapse/refractory disease.

Conclusion

The combination of sorafenib, vorinostat, and bortezomib when given with a 2-week on, 1-week off schedule is safe with minimal side effects, and tolerable as an outpatient regimen for the treatment of poor-risk AML. Encouraging responses with this regimen are seen in these patients. The phase II portion of the study is currently ongoing. Correlative studies to further elucidate the molecular attributes of efficacy of this regimen in poor-risk AML are underway. Updated results will be presented.