Alteminostat (CKD-581), a novel hydroxamate-based pan-HDAC inhibitor, increases acetylation of histones and other proteins involved in multiple oncogenic pathways. It modulates gene expression involved in cell-cycle regulation, differentiation, and apoptosis. Altemonstat in combination with lenalidomide and dexamethasone demonstrated promising anti-cancer efficacy both in vitro and in vivo studies, including xenograft models of multiple myeloma (MM). In addition, it was well tolerated in patients with lymphoma and MM refractory to standard therapy. On the basis of this background, we conducted a phase I dose-finding study of alteminostat in combination with lenalidomide and dexamethasone in relapsed MM patients.
Subjects with MM who had relapsed after at least one prior treatment were infused alteminostat iv (90, 120, or 160 mg/m2, level 1-3, respectively once weekly for 3 weeks out of a 4-week cycle in a standard 3+3 dose-escalation, phase 1 design, combined with lenalidomide 25 mg on day 1-21 and dexamethasone 40 mg on day 1, 8, 15, 22 in a 28-day cycle
As of July 11th, 2019 the study has enrolled 10 patients with relapsed MM to Level 3. The median age was 56 (range 46-64), and the median number of previous regimens received was 2.5 (range 1~8). Based on the data cut off day, no dose-limiting toxicities were identified. 2 patients were in progress on the maximum planned dose of 160 mg/m2. The most common (>20% of subjects) drug-related adverse events (AEs) were thromobcytopenia (80%), neutropenia (60%), anemia (50%), muscle spasms (50%), fatigue (30%), upper abdominal pain (30%), and constipation (30%). Serious adverse drug reaction was not reported. AEs related with cardiac disorder have not been observed. The most common ≥Grade 3 hematologic AEs were neutropenia (70%), thromobcytopenia (60%), and anemia (60%). The most common ≥Grade 3 non-hematologic AEs are pneumonia (40%). One patient at dose level 2 died from pulmonary embolism after pneumonia. Two of ten patients had exposed to lenalidomide before participating in this clinical trial. The median cycle was 3 in level 1, 4 in level 2 and 2 in level 3, while level 3 is still in progress. The overall response rate, defined as achieving more than partial response (PR), for all patients was 70%, including 10% stringent complete response (sCR), 10% CR, 20% very good PR and 30% PR. The median duration of response was 236 days and median progression-free survival was 232 days.
Alteminostat, a novel hydroxamate-based pan-HDAC inhibitor, can be combined safely with lenalidomide and dexamethasone, demonstrating significant clinical activity in subjects with MM. Enrollment is ongoing and full phase 1 will be updated and presented.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.