SAN DIEGO, CA—Use of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone is promising for patients with bortezomib-refractory MM, results PANORAMA 2, a single arm, Phase 2 study presented at the 53rd American Society of Hematology Annual Meeting and Exposition have found.
Panobinostat is an oral pan-deacetylase inhibitor that intensifies acetylation of proteins involved in various oncogenic pathways. Clinical responses (≥minimal response [MR]) have been seen in 65% of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib (including patients with bortezomib-refractory disease) in a Phase 1 study.
Patients in this study were either relapsed or were bortezomib-refractory, defined as having received ≥2 prior lines of therapy including an immunomodulary drug (thalidomide or lenalidomide) and progression on or within 60 days of the last bortezomib-based therapy. Patients were treated in two phases. The first treatment phase included eight three-week cycles of oral panobinostat 20mg on Days 1, 3, 5, 8, 10, 12; intravenous bortezomib 1.3mg/m2 on Days 1, 4, 8, 11; and oral dexamethasone 20mg on the day of and after bortezomib. The second treatment phase was reserved for patients displaying clinical benefit (≥stable disease) and included six-week cycles of panobinostat 20mg three times weekly, two weeks on and one week off (repeating), bortezomib 1.3mg/m2 on Days 1, 8, 22, and 29, and dexamethasone 20mg on the day of and after bortezomib, given until disease progression.
The study’s primary endpoint is overall response (OR=complete response [CR] + near CR [nCR] + partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first eight cycles of Phase 1 treatment. Four or more PR in 24 patients were needed in stage 1 in order for the study to advance to stage 2.
A total of 55 patients were enrolled in the trial. Patients received a median of four (range 2–14) prior regimens; most patients (69%) had prior autologous stem cell transplant.
At the time of assessment, OR was observed in 16 patients (29%; 0 CR, 2 nCR, 14 PR). Clinical benefit (OR + minimal response [MR]) was documented in 27 patients (49%), and very good PR (VGPR) in three patients (6%). Stable disease was observed in two patients and progressive disease in 10 patients. Mean duration of the study is 4.7 months (range <1–12.5). Sixteen patients have completed the first eight cycles and have entered the second phase of the study: 10 patients remain in phase 2 and two patients have completed ≥12 cycles.
Any grade common adverse events included fatigue (63%), treatment-emergent neuropathy (24%), and asthenia (14%) and were predominantly mild. The most common Grade 3/4 adverse event was thrombocytopenia (53%); this was managed with dose reductions/interruptions and were observed less when panobinostat was dosed two weeks on and one week off compared with the weekly schedule.
The data from this trial, along with that of a Phase 3 study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM, will additionally characterize the budding use of panobinostat in the treatment of patients with MM, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, MA, stated.