Final Results of the Phase II SAPHIRE Trial of Resminostat (4SC-201) in Patients with Relapsed/Refractory Hodgkin Lymphoma

Abstract

2675 Background: Resminostat is an oral pan-histone deacetylase (HDAC) inhibitor that has shown anti-tumor activity in a broad panel of preclinical models and revealed a favorable safety and efficacy profile in a first-in-man phase I study in patients (pts) with various solid tumor types. Resminostat is currently in phase II clinical development in pts with hepatocellular carcinoma (HCC), colorectal carcinoma (CRC) and Hodgkin Lymphoma (HL). Methods: The SAPHIRE trial involved HL pts who relapsed or progressed after prior therapy including high-dose chemotherapy and autologous stem cell transplantation (ASCT) or were refractory to treatment. The study was designed as an open-label, single-arm, international trial consisting of two recruitment stages according to the Simon Minimax design. Resminostat was administered orally at a once daily dose of 600 mg during the 1st recruitment stage and at a higher daily dose of 800 mg in the 2nd stage. Patients were treated in cycles of five consecutive days followed by a nine-day treatment-free period (5+9 schedule), constituting one 14 day cycle. Patients underwent assessment of their disease status by computed tomography in combination with positron emission tomography (PET/CT) after Cycle 3 and Cycle 6 and thereafter every fourth cycle during an optional extension phase of the study in which pts continued on treatment until disease progression. The primary endpoint of the study was defined as the overall objective response rate (ORR) based on the best response during treatment. Response was defined as complete response (CR) or partial response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) or as partial metabolic response (PMR) according to EORTC criteria (Young 1999). Secondary endpoints include time to response (TTR), duration of response (DOR), progression free survival (PFS), overall survival (OS), safety and tolerability and the evaluation of drug regulated biomarkers including the CC thymus and activation related chemokine TARC. Results: The enrolment was complete in June 2011 with 37 pts at 5 study sites available for safety evaluation. Median age of the safety population was 34 years (range 19–64 years). 21 pts (57%) had ASCT and 14 pts (67% of all ASCT pts) relapsed within one year after ASCT. 26 patients (70%) had ≥ 5 prior lines of therapy; median number of prior regimens was 6 (range 1–12). Stage of disease according to Ann Arbor classification at baseline was: 6 pts with stage 2, 4 pts with stage 3 and 27 pts with stage 4. 17 pts had B-symptoms at baseline (46%). Dosing with 600 mg or 800 mg resminostat was well tolerated with common treatment-related grade 2–3 AEs being anemia and thrombocytopenia that were well manageable by dose modification. Assessment of PK parameters confirmed the favorable profile of the oral administration route and dose dependent resminostat plasma concentrations. As of August 2011 out of 37 pts 35 pts had ≥ 1 post-baseline PET/CT tumor assessments and 2 pts discontinued early due to AE. Two out of 35 pts are still on study therapy in the optional extension phase after Cycle 6. Up to now 33 pts were evaluated centrally for tumor response. Of those, 11 pts qualified as responders (ORR=33%). Responders included 1 complete response (CR), 3 partial responses (PR) and 7 partial metabolic responses (PMR). Median time to response was 3 cycles. Additional 7 patients achieved stabilization of the disease. Thus, in total 18 pts (55%) obtained a clinical benefit from resminostat monotherapy. Conclusion: Results of the SAPHIRE study demonstrated substantial anti-tumor activity of the HDAC inhibitor resminostat in heavily pre-treated HL patients. Resminostat can be safely administered as oral monotherapy up to 800 mg once daily in a 5+9 day treatment schedule. Disclosures: Walewski: 4SC AG: Consultancy. Hauns:4SC AG: Employment. Mais:4SC: Employment. Henning:4SC AG: Employment. Hentsch:4SC AG: Employment.

First-in-human, Pharmacokinetic and Pharmacodynamic Phase I Study of Resminostat, an Oral Histone Deacetylase Inhibitor, in Patients with Advanced Solid Tumors

“…Of interest, belinostat, an inhibitor of HDAC class I and II enzymes, demonstrated clinical activity in a phase II study of 32 patients with recurrent or metastatic thymoma and thymic carcinoma (25). Evaluation of resminostat as monotherapy in a Phase II clinical trial of relapsed/refractory Hodgkin lymphoma patients after high dose chemotherapy and autologous hematopoietic stem cell transplantation has yielded encouraging results; in a heavily pre-treated group of patients (median of 6 prior lines of therapy), the reported objective response rate by an independent central review board in an interim analysis was 33% (11 of 33 evaluable patients) by the Cheson criteria with a clinical benefit rate of 55% (18 of 33 patients) (26, 27). Resminostat is also being developed in combination with sorafenib in hepatocellular carcinoma (28) and with standard FOLFIRI treatment in colorectal cancer (ClinicalTrials.gov NCT01277406).…”

“…Resminostat is also being developed in combination with sorafenib in hepatocellular carcinoma (28) and with standard FOLFIRI treatment in colorectal cancer (ClinicalTrials.gov NCT01277406). Overall, emerging tolerability and efficacy data from these ongoing studies are promising and the final results are awaited (27, 28).…”

Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

“…Synergistic effects were observed when it was used in combination with melphalan, bortezomib and S-2209 [ 76 ]. In a Phase II SAPHIRE trial, resminostat was also tested in relapsed or refractory Hodgkin Lymphoma (HL) [ 77 , 78 ]. Assessment of disease status was carried out by computed tomography in combination with positron emission tomography (PET/CT).…”

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

“…Another alkenyl type small molecule HDAC inhibitor, Panobinostat, received FDA approval in 2015 for the treatment of patients with multiple myeloma [70]. The FDA approvals of belinostat and panobinostat opened an avenue for the exploration of alkenyl type drug candidates and subsequently, resminostat [199][200][201][202] and pracinostat [203][204][205] were identified that are now undergoing clinical stage investigation. Givinostat [206][207][208], abexinostat [209,210], AR-42 [211,212] and bisthianostat [213,214] represents the chemically related compounds bearing a more rigid phenylhydroxamic acid while quisinostat [215][216][217], nanatinostat [218,219] and fimepinostat [220] containing a more polar pyrimidinyl heteroaromatic EED-EZH2 protein-protein interaction (PPI) disruption leads to loss of H3K27me3-stimulated PRC2 activity and prevents H3K27 trimethylation, which ultimately leads to decreased tumor cell proliferation in EZH2-mutated and PRC2-dependent cancer cells.…”