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

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).

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.

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.

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.

Walewski:4SC AG: Consultancy. Hauns:4SC AG: Employment. Mais:4SC: Employment. Henning:4SC AG: Employment. Hentsch:4SC AG: Employment.