Bernd Hentsch

Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma – The SHELTER study

BACKGROUND & AIMSnNo established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib.nnnMETHODSnPatients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat.nnnRESULTSn57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival.nnnCONCLUSIONSnThe combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications.nnnLAY SUMMARYnNo established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib.nnnCLINICAL TRIAL REGISTRATIONnThe clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.

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

Purpose: This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. Experimental Design: Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. Results: Nineteen patients (median age 58 years, range 39–70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. Conclusions: Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days. Clin Cancer Res; 19(19); 5494–504. ©2013 AACR.

Oral small molecule modulators of p300/CBP to reprogram cancer cells and reactivate the p53 pathway in HPV-associated carcinomas.

e14581Background: Dysregulation of the basal cellular transcription machinery is a fundamental feature of cancer. E1A binding protein (p300) and CREB binding protein (CBP) are two closely related p...

Tu1875 Vidofludimus Induces p53-Mediated Apoptosis in Activated T Cells and Inhibits IL-17A and IL-17F Expression Decoupled From Lymphocyte Proliferation

Background: Vidofludimus is a novel oral immunomodulator that has shown substantial activity in various autoimmune models and is currently clinically developed for inflammatory bowel disease (IBD). Induction of apoptosis in mucosal T cells from IBD patients is a relevant therapeutic mechanism since several effective IBD drugs like 6-mercaptopurine (6-MP) were shown to induce apoptosis in activated T cells. The interleukin-17 (IL-17) cytokine family is involved in many inflammatory diseases and increased IL-17 levels have been found in inflamed gut mucosa and serum of IBD patients. Especially IL-17F plays a crucial role in the pathogenesis of IBD. Vidofludimus has been described to inhibit IL-17A and IL-17F In Vitro and In Vivo in IBDmodels. In this study the apoptosis inducing capacity of vidofludimus and its inhibitory effect on IL-17 expression by activated T cells in relation to its effect on cell proliferation have been investigated. Methods: PBMC isolated from blood of healthy volunteers and stimulated with phytohaemagglutinin (PHA) were analyzed for cell cycle arrest, IL-17 expression, cell proliferation (BrdU incorporation), and apoptosis induction (AnnexinV/PI staining) by flow cytometry. P53 accumulation was measured by ELISA, IL17A and IL-17F gene expression by RT-PCR. Apoptosis induction was also analyzed in Jurkat cells. Results: Vidofludimus is a potent inducer of apoptosis in PHA activated T cells and Jurkat cells, comparable to reference compound 6-MP. The active metabolite of leflunomide was less active, particularly in Jurkat cells. G1/S arrest and strong accumulation of p53 precede apoptosis induction. Vidofludimus inhibits production of IL-17AA/AF and IL-17FF in a dose-dependent fashion with IC50 values between 3 and 10 μM; this correlates well with reduced gene expression patterns for IL-17 subtypes 20 h after PHA stimulation. This effect is decoupled from T cell proliferation as significant inhibition of IL-17 production is observed already 24 h after stimulation whereas inhibition of T cell proliferation by vidofludimus as judged by BrdU incorporation is not detectable earlier than 48 h after activation. Conclusions: Vidofludimus induces cell cycle arrest, p53 accumulation and subsequent apoptosis in activated T cells. Furthermore, it inhibits production of IL-17 cytokines decoupled from its effects on T cell proliferation. The combination of both effects might substantially contribute to the beneficial effects of vidofludimus observed in IBD patients as previously reported.

The effect of 4SC-207, a novel antimitotic agent, on multidrug-resistant cell lines.

e14090 Background: 4SC-207 is a novel small molecule with strong anti-mitotic activity. In this study the potency on in vitro cell proliferation, including chemotherapeutically resistant P-gp-expressing cells, was investigated. These observations were confirmed in in vivo xenograft tumor models.nnnMETHODSnIn vitro proliferation assay: 4SC-207 was tested on a panel of 50 ATCC cell lines. After a 24 h pre-growth period cells were incubated with 4SC-207 at different concentrations for 72 hours. After treatment cells were precipitated and stained with 0.4% wt/v sulforhodamine B solution in 1% acetic acid. Measurement of optical density was performed at 520 nm. Proliferation inhibition was determined as growth inhibition of 50% (GI50). In vivo xenograft model: 4SC-207 was tested both i.v. and p.o. in a xenograft NMRI mouse model using human colon adenocarcinoma cell line RKOp27. In the i.v. study 4SC-207 was administered at a dose of 40 mg/kg BID on days 1-7 and SID on days 8 and 11-14. In the p.o. study 4SC-207 was administered at a dose of 80 mg/kg SID on days 1, 2, 6, 7, 11, and 12. Endpoints consisted of tumor volume and body weight and hematologic parameters.nnnRESULTSnIn vitro proliferation assay: 4SC-207 effectively inhibited the proliferation of most tested tumor cell lines with average GI50 values between 4 nM and 12 nM. 4SC-207 was also active on cell lines such as human colon cell lines HCT-15 and DLD-1 which display P-gp up-regulation and are known to be resistant to a large set of conventional anti-cancer agents (e.g. taxanes). In vivo xenograft model: 4SC-207 displayed a strong anti-tumor activity. Treatment with 4SC-207 induced complete tumor stasis (i.v.: Treated/Control = 0.09; p.o.: T/C = 0.1). Effects on body weight were mild and other signs of overt toxicity were not observed.nnnCONCLUSIONSn4SC-207 is a highly potent, novel anti-mitotic compound with strong in vitro and in vivo anti-tumor activity. 4SC-207 is also active on P-gp expressing tumor cells and offers the opportunity for treatment of hematological and solid tumor types which are resistant to standard anti-cancer agents.