HDAC6 Inhibitor Shows Activity in Relapsed, Refractory Myeloma

The combination of bortezomib and dexamethasone with 160 mg daily ricolinostat, a selective histone deacetylase 6 (HDAC6) inhibitor, was well tolerated and active in patients with relapsed/refractory multiple myeloma, according to the results of a phase I/II study published in Clinical Cancer Research.

According to researchers led by Dan Vogl, MD, MSCE, of the Perelman Center for Advanced Medicine, these findings “show that the combination of HDAC6-selective inhibition using ricolinostat with the proteasome inhibitor bortezomib overcomes bortezomib resistance in relapsed multiple myeloma, with a favorable safety profile that offers potential advantages compared to nonselective histone deacetylase inhibition.”

The three-part study included patients with relapsed or refractory multiple myeloma. During parts 1 and 2 there was sequential group dose-escalation of ricolinostat as monotherapy (part 1) and in combination with bortezomib and dexamethasone (part 2). Part 3 of the study was an expansion cohort used to explore a once daily dose of ricolinostat instead of a twice daily dose. All patients had received prior bortezomib and 33% in the single-agent cohort and 63% in the combination cohorts were refractory to the drug.

The researchers found that treatment with single-agent ricolinostat did not produce significant toxicity, but also produced no clinical response in the cohort. They did not explore a dose higher than 360 mg twice daily because there was a plateau in exposure at the 160 mg twice daily dosage. Of the 15 patients, 6 had stable disease and none had a response.

Combination therapy of ricolinostat with bortezomib and dexamethasone was well-tolerated during the dose-escalation portion of the study, but led to dose-limiting diarrhea in an expansion cohort at the dose of 160 mg twice daily. Almost one-third (29%) of patients in this expansion cohort were hospitalized for reasons potentially related to diarrhea and dehydration.

“Because of a concern that this represented excess toxicity with twice daily dosing, we enrolled a second expansion cohort at a lower dose of ricolinostat (160 mg qd) to better understand the relationship between dose and both toxicity and efficacy,” the researchers wrote.

In the second expansion cohort testing combination therapy with 160 mg ricolinostat once daily, the therapy was well tolerated. Patients in this group experienced less severe hematologic, gastrointestinal, and constitutional toxicities compared with prior published data on non-selective HDAC inhibitors.

At a once daily dosage, combination therapy resulted in an overall response rate of 37%. Among patients who were refractory to bortezomib, the overall response rate was 14%.

The researchers noted that this trial was initiated prior to the US Food and Drug Administration approval of panobinostat, a pan-HDAC inhibitor, that was approved with a black-box warning  associated with its increased risk for severe diarrhea and cardiac events.

“Our investigation of ricolinostat is predicated on the theory that the efficacy of HDAC inhibition in combination with proteasome inhibitors is due to inhibition of HDAC6-mediated trafficking of polyubiquitinated proteins to the aggresome/autophagy pathway, while the adverse effects seen with other HDAC inhibitors are due to adverse alterations in gene expression due to inhibition of class I HDACs,” the researchers wrote. “Ricolinostat does retain a lower level of class I HDAC inhibition compared to pan-HDAC inhibitors, but our data support the concept that ricolinostat’s reduced inhibition of class I HDACs results in an improved therapeutic window.”