EFFICIENT HDAC INHIBITION AND TARC REDUCTION IN PATIENTS WITH REFRACTORY HODGKIN LYMPHOMA TREATED WITH RESMINOSTAT - PK/PD DATA FROM THE PHASE II SAPHIRE STUDY

Sborník

Background. Resminostat (R) 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. R is currently in phase II clinical development in pts with hepatocellular carcinoma (HCC), colorectal carcinoma (CRC) and Hodgkin lymphoma (HL). Methods. The open label, single arm, phase II SAPHIRE trial included HL patients who had progressed after prior therapy or were refractory to treatment. R was administered once daily at 600 mg or 800 mg. Pts were treated in cycles of 5 consecutive days followed by a 9 day treatment-free period (5+9 schedule), constituting a 14 day treatment cycle. Pts underwent assessment of their disease status by PET/CT. Primary endpoint of the study was the overall objective response rate (ORR). Secondary endpoints included efficacy, safety and tolerability and the analysis of pharmacokinetics of both doses for up to 6 h post-dose during the 1st and 3rd treatment cycle. Similarly, the effect of different doses of R on pharmacodynamic biomarkers such as HDAC enzyme inhibition and changes in expression levels of selected target genes was determined in peripheral blood cells (PBMC). In addition, plasma levels of the CC thymus and activation-related chemokine TARC (CCL17), a potential prognostic factor in HL, were determined. Results. The SAPHIRE study enrolled 37 patients of which 35 were eligible for efficacy evaluation. R at 600 mg or 800 mg daily dose was well tolerated with grade 2- 3 anemia and thrombocytopenia in 35% and 27% of pts as most frequent AEs. Peak plasma levels of R were achieved at T_max = 2 h post-dose in both 600 mg (n=19) and 800 mg (n=18) dose cohorts. C_max and AUC increased proportionally to dose. Single and repeat PK profiles in both dose cohorts were comparable. Inhibition of HDAC enzymatic activity was time dependent and fully reversible within 72 h post-dose and reached a maximum of up to 94% inhibition at about 2 h post-dose corresponding to R peak plasma levels. Baseline TARC plasma levels of median 8400 pg/ml (range 35 pg/ml to >100 000 pg/ml) were substantially reduced after three cycles of R to a median of 2800 pg/ml, with a reduction of ³50% in 12 of 27 pts tested. Lower baseline TARC plasma levels were associated with clinical benefit to R treatment. Expression analysis of a set of 10 genes in pts PBMCs showed a correlation to drug plasma levels with strongest effects on transcription 5 h post-dose reflecting the delayed biological response to target inhibition. Conclusions. PK/PD data from the phase II SAPHIRE study indicate good bioavailability and efficient in vivo HDAC inhibition by resminostat at daily doses of 600 mg and 800 mg. Resminostat treatment also resulted in biological relevant downstream effects like transcriptional modulation and TARC plasma level reduction in heavily pre-treated HL patients. These findings may now be explored for their potential to predict clinical responses.

Haematologica, 2012; 97(s1):  16