SummaryInhibition of histone deacetylase (HDAC) is a promising mechanism for novel, anti-myeloma agents. We investigated the effects of the novel HDAC inhibitor resminostat on multiple myeloma (MM) cells in vitro. Resminostat is a potent inhibitor of HDACs 1, 3 and 6 [50% inhibitory concentration (IC 50 ) = 43-72 nmol/l] representing HDAC classes I and II and induces hyperacetylation of histone H4 in MM cells. Low micromolar concentrations of resminostat abrogated cell growth and strongly induced apoptosis (IC 50 = 2AE5-3 lmol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 lmol/l, resminostat inhibited proliferation and induced G0/G1 cell cycle arrest in 3 out of 4 MM cell lines accompanied with decreased levels of cyclin D1, cdc25a, Cdk4 and pRb as well as upregulation of p21. Resminostat decreased phosphorylation of 4E-BP1 and p70S6k indicating an interference with Akt pathway signalling. Treatment with resminostat resulted in increased protein levels of Bim and Bax and decreased levels of Bcl-xL. Caspases 3, 8 and 9 were activated by resminostat. Furthermore, synergistic effects were observed for combinations of resminostat with melphalan and the proteasome inhibitors bortezomib and S-2209. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor.
262 Background: Resminostat (4SC-201), an oral pan-HDAC inhibitor, is in clinical development in a variety of cancer indications. The SHELTER study aims to evaluate safety, tolerability and efficacy in HCC patients (pts) exhibiting progressive disease under sorafenib first-line therapy. Methods: Pts with advanced HCC, (BCLC B or C) are included in a multi-center, open-label, two-arm parallel group trial. Radiologic progression under sorafenib is determined acc. to RECIST by central review prior to study entry. For Arm A, dose escalation of resminostat and sorafenib is performed to determine the MTD. Resminostat is administered orally once-daily in a “5+9” schedule, consisting of 5 consecutive treatment days followed by a 9-day rest period resulting in 14 day cycles on dose levels of 200 (DL1), 400 (DL2) and 600 mg (DL3+4), either combined with continuously taken sorafenib at 400 (DL1-3) or 800 mg (DL4) (Arm A), or as resminostat monotherapy (600 mg, Arm B). Primary objective is to determine progression-free survival after 12 weeks (w) (6 cycles). Secondary objectives include safety, tolerability, tumor response, TTP, OS, PK, biomarkers. Results: To date, 39 pts were treated with 600 mg resminostat alone or on DL1-4 in combination with sorafenib. Up to now, no DLT occurred in 5 pts treated on DL4. Most frequently AE observed include CTC grade 1-2 gastrointestinal complaints such as nausea and vomiting and skin disorders like rash, pruritus and HFSR. CTC Grade 3-4 toxicity documented in SAE reports consisted mainly of no-hematological events and was mostly related to the tumor disease. Interim results revealed that 15 out of 27 pts (56%) assessed after 6 w of treatment, and 11 out of 24 pts after 12 w displayed SD. In one patient treated on DL2, SD persisted for more than 1 year along with good long-term tolerability. Conclusions: Preliminary clinical data show a favorable drug profile of resminostat either in mono or in combination treatment with sorafenib. No DLT was observed on the highest DL of the combination therapy up to now. Initial data on toxicity and therapeutic activity to overcome resistance to sorafenib are promising and will be updated for the meeting.
4115 Background: Resminostat (R), an oral HDAC inhibitor, was studied in the SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts) refractory to sorafenib (S). R was explored as monotherapy and within a novel resensitization approach to overcome tolerance to S by the combination of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were included in a multi-center, two-arm trial. Radiologic progression under S firstline therapy had to be confirmed by central review (RECIST) prior to study entry. A dose escalation of R (range 200 to 600 mg) combined with S (400 or 800 mg) was performed. Arm A investigated the drug combination (R+S), Arm B the monotherapy of R (600 mg). Primary objective was the progression-free survival rate (PFSR) after 12 weeks (w). Secondary objectives included safety, tolerability, tumor response, PFS, TTP, OS and the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme inhibition, histone acetylation and gene expressions in peripheral blood. Results: 50 pts were enrolled, dose escalation determined 600 mg R and 400 mg S for Arm A. Clinical activity results of 15 evaluable pts from combination treatment revealing a PFSR of 66.6% after 12 w, not all patients in Arm B already reached the 12 w staging. Most frequent AE were CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash, pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of non-hematological events mostly related to tumor disease. Plasma concentrations of both drugs correlated with administered doses and were in the expected range without obvious influence of preexisting liver disease. BM investigations revealed effective target modulation by R in both arms. Conclusions: The primary study objective was achieved for both treatment arms. R demonstrated a favorable PK, safety and tolerability profile, even in combination with S and despite preexisting liver disease, includig cirrhosis. The observed clinical activity emphazises the resensitizing activity of R by an epigenetic mode-of-action to overcome tolerance to S and warrants further development, in particular for combination therapy in both, first and second line HCC treatment.
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