Final Results of Phase I/II Study of Combination of Sorafenib, Vorinostat, and Bortezomib in Acute Myeloid Leukemia with FLT3-ITD Mutation or Poor-Risk Cytogenetics

Introduction

We report the final results of a phase I/II study of combination of targeted agents sorafenib, vorinostat, and bortezomib (SorVorBor) in poor-risk AML. Data from the phase I part of this study have previously been reported by our group. The rationale for SorVorBor phase I/II study was based on findings of an initial phase I study, at Indiana University, of the combination of sorafenib and vorinostat (SorVor) in patients with AML. The SorVor study suggested a potential benefit in terms of response to treatment in two patient groups: (i) patients with FLT3-ITD mutation, and (ii) patients with poor-risk cytogenetics (monosomy 5 or 7, or complex profile). The SorVor study also suggested a potential synergistic action offered by inhibition of p52NFKB , a downstream target of proteasome inhibition. These findings laid the hypothetical ground for the addition of bortezomib to SorVor, aiming at achieving synergism by proteasome inhibition, in the SorVorBor study (NCT01534260).

Methods

Adult patients with an ECOG performance status 0-2, adequate kidney and liver function, and a diagnosis of relapsed/refractory AML or those age 60 or older with untreated disease were enrolled. Patients had to have FLT3-ITD mutation and/or poor-risk cytogenetics (monosomy 5, monosomy 7 or complex cytogenetics). Phase I consisted of cohorts with escalating doses of sorafenib, vorinostat, and bortezomib. An MTD was not achieved in the phase I part of this study, therefore the safe dosing determined for the phase II part was: sorafenib 400 mg BID, vorinostat 200 mg BID (both for 14 days), and bortezomib 1.3 mg/m² IV on days 1, 4, 8, and 11, every 21 days. Response was evaluated based on the revised guidelines by the International Working Group for AML.

Results

Seventeen patients were enrolled in the phase I part and 20 in the phase II. Three patients in cohort 5 of the phase I part received a similar dosing to patients in the phase II; therefore, the data from this cohort were added to the phase II data for response analysis. A total of 23 patients were consequently considered for analysis having received the optimal dosing previously delineated. Fourteen patients were evaluable for response after completing at least one cycle of therapy. Rest of the patients either did not complete the first cycle or did not have a bone marrow examination performed for variety of reasons. Evaluable patients received between one to three cycles of treatment. The median age was 58 years (24-76). One patient (7.1%) had previously untreated disease while 13 patients (92.9%) had relapsed and/or refractory disease. Seven patients (50.0%) had received three or more lines of therapy. One patient (7.1%) had relapsed following hematopoietic stem cell transplantation. Fifty percent of patients had FLT3-ITD mutation and 57.1% carried poor-risk cytogenetics. The most common toxicities were gastrointestinal disturbances (64.2%) including diarrhea, nausea, or vomiting reaching grade 2 in 14.2% of patients. No grade 3 or 4 gastrointestinal toxicities were observed. Other toxicities included fatigue (31.3%), rash (21.4%), and neutropenic fever (7.1%); none was greater than grade 2. Response was observed in four out of the 14 patients (28.6%) including one patient (7.1%) achieving CR, one patient (7.1%) achieving CRi, and two patients (14.3%) achieving PR. All four patients who responded had FLT3-ITD mutation. Eight out of the 10 non-responders (80.0%) and none of the four responders had poor-risk cytogenetics. All four responders were previously treated and had relapsed and/or refractory disease. The characteristics of the participants and their response are summarized in Table 1. Comparing results of the SorVorBor study to those from SorVor study suggests a lower overall response rate in the SorVorBor study (28.6% versus 53.8%).

Conclusion

The SorVorBor combination was safe and tolerable in patients with relapsed/refractory AML. There was no dose limiting toxicity per the phase I part. A clinical response was observed in 60% of patients with FLT3-ITD mutation and none with poor-risk cytogenetics. The addition of bortezomib to SorVor did not demonstrate a clinically significant effect.

Table 1

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Table 1

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