A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma

Abstract

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair

“…However, toxicity has been a concern in the clinical settings. For example, the serious hematological toxicity observed with the combination of panobinostat and melphalan in MM precluded the demonstration of clinical activity in this particular clinical trial [21]. In our ex vivo experiments, we observed a therapeutic window for plasma cells as compared with lymphocytes, which is further confirmed in in vivo studies, in which we showed the clear efficacy of the compound with an acceptable toxicity.…”

“…Preclinical data have shown the synergy of panobinostat with melphalan [18] and that of entinostat with bendamustine [19]. Unfortunately, this effect has not been observed in the clinical setting, partly due to the hematological toxicity of these combinations [20, 21]. Our hypothesis is that this hybrid molecule may be able to overcome these caveats.…”

Combined use of bortezomib, cyclophosphamide, and dexamethasone induces favorable hematological and organ responses in Japanese patients with amyloid light-chain amyloidosis: a single-institution retrospective study

“…Other agents, including elotuzumab (anti-CS-1 antibody), anti-CD38 antibody, and panobinostat, which are newly available to treat MM might be effective for ALA [23][24][25][26].…”

Panobinostat: a review of trial results and future prospects in multiple myeloma

“…Panobinostat was combined with oral melphalan in a Phase I/II trial of 40 RR MM patients [64]. The MTD was 20 mg of panobinostat (days 1, 3 and 5 of week 1 only for each 28-day cycle) and 0.05 mg/kg melphalan (days 1, 3 and 5 of each cycle).…”