San-Miguel and colleagues reported safety and preliminary efficacy phase 1 data for the all-oral regimen consisting of the novel proteasome inhibitor (PI) ixazomib plus the pan-deacetylase inhibitor panobinostat and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM).1 An every-other-week dosing of panobinostat was applied in this trial since the dosing schedule used in the pivotal PANORAMA 1 trial (20 mg 3 times a week, 2 weeks on, 1 week off) was associated with clinically significant adverse events (AEs), including severe diarrhea and unexpected cardiac events; the combination of panobinostat plus bortezomib/dexamethasone in the pivotal trial resulted in significant progression-free survival prolongation compared with control.2
In this phase 1 trial, the standard 3+3 dose-escalation design was used to enroll 11 eligible patients to receive ixazomib (3 mg or 4 mg; on days 1, 8, and 15 every 28 days) plus panobinostat (20 mg on day 1, 3, 5, 15, 17, 19) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16). Eligible patients must have received at least 2 prior regimens that had included a PI and immunomodulatory drug (IMiD). Patients had received a median of 5 prior regimens (range, 2-10), and all were refractory to their last regimen. Dose escalation to dose level 2 occurred without dose-limiting toxicity; no serious AEs were observed and no dose reductions of panobinostat or ixazomib were needed. No nonhematologic grade 3/4 AEs were reported; 3 patients experienced grade 3 hematologic toxicities, including neutropenia (n = 2) and thrombocytopenia (n = 1). Other AEs of interest included diarrhea, nausea, fatigue, anorexia, and arthralgia, all of which were of grade 1/2 severity. Median QTcF was prolonged on average by 4.3% from a baseline level of 405 msec (range, 378-430); 1 patient experienced transient grade 1 QTcF prolongation to 552 msec. Best responses were a minor response in 2 patients and a partial response in 1 patient, who had progressed on prior PI/IMiD combination therapy at study entry. Stable disease was observed in 4 patients. Based on these results, it was concluded that the all-oral combination of ixazomib plus panobinostat and dexamethasone was well-tolerated and demonstrated clinical activity in heavily pretreated patients with MM and progressive disease on PI/IMiD combinations.
- San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.
- Reu FJ, et al. ASH 2015. Abstract 4221.