Date: 2011-09-06
Type of information: Results
phase: 2
Announcement: results
Company: 4SC (Germany)
Product: resminostat (oral pan-histone deacetylase (HDAC) inhibitor)
Action
mechanism: enzyme inhibitor/histone deacetylase inhibitor. HDAC inhibitors modify the DNA structure of tumour cells to cause their differentiation and programmed cell death (apoptosis) and are therefore considered to offer a mechanism of action that has the particular potential to halt tumour progression and induce tumour regression.
Disease: relapsed/refractory Hodgkin's Lymphoma
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The SAPHIRE trial included HL patients that had relapsed after high dose chemotherapy and/or autologous stem cell transplantation (ASCT) or had become refractory to treatment. The study was designed as an open-label, single-arm, international trial consisting of two recruitment stages according to the Simon's Minimax design. Resminostat has been administered orally at a once daily dose of 600 mg during the 1st recruitment stage and due to its good tolerability at a higher daily dose of 800 mg in the 2nd stage. Patients were treated in 14-day cycles of five consecutive days followed by a nine-day treatment-free period (5+9 schedule). 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 follow-up period in which patients could continue treatment until disease progression. The primary endpoint of the study was defin ed as the overall objective response rate (ORR) based on the best objective response during treatment. 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 assessment of TARC levels.
Latest
news: 4SC AG has announced positive topline data from its Phase II SAPHIRE trial with resminostat, its oral pan HDAC inhibitor, in patients with relapsed/refractory Hodgkin's Lymphoma (HL). Resminostat monotherapy exhibited substantial anti-tumour activity, including complete and partial tumour responses. Analysis of tumour response assessments revealed that the study achieved its primary endpoint. Furthermore the study verified the drug to be safe and well tolerated in this advanced stage patient population.
In June 2011 the SAPHIRE trial completed patient enrolment. 33 patients have been evaluated for tumour response which, according to the study protocol, represents the targeted number of patients required for efficacy analyses. Central assessment of patient tumour data by an independent expert review board revealed objective tumour responses in 11 patients, constituting a 33.3% overall response rate (ORR) and thereby successfully achieving the pre-defined requirements of the primary endpoint of the study. This ORR of 33.3% together with a clinical benefit recorded in total for 54.5% of the patients (disease control rate) demonstrates the substantial anti-tumour activity of resminostat monotherapy in an advanced and heavily pre-treated Hodgkin's Lymphoma patient population for which there is currently no established standard therapy available. Prior to study entry, the patients enrolled received a median of 6 treatments consisting of various chemo- and radiation therapies including autologous stem cell transplantation in 57% of the cases.
The clinical activity of resminostat was measured through PET/CT, the combination of positron-emission tomography (PET) and computer tomography (CT). Study responders included 1 complete response (CR) and 3 partial responses (PR) according to Cheson criteria. Furthermore, 7 patients experienced partial metabolic responses (PMR) according to EORTC criteria. An additional 7 patients achieved stabilization of their disease. Thus, in total 18 of 33 patients, representing 54.5% of all patients evaluated for efficacy, received a clinical benefit from resminostat treatment. Additional two patients are currently continuing on study therapy in the optional follow-up phase, and have therefore not been subject to final response evaluation by the independent review board.
Treatment with resminostat was generally well tolerated with common grade 2-3 adverse events3 mainly being of gastrointestinal (nausea) or hematological (anemia, thrombocytopenia) origin. All adverse events were well manageable by dose modification or symptomatic treatment. Assessment of pharmacokinetic (PK) parameters confirmed the favorable profile of the oral administration route and dose dependent resminostat plasma concentrations.
The reported Phase II SAPHIRE trial for resminostat as a third-line therapy in Hodgkin's lymphoma is still ongoing as two patients are continuing on study therapy in the optional follow-up phase beyond 12 weeks of treatment.
