C125
A first-in-man, dose-escalating Phase I study of 4SC-201, a new oral histone deacetylase (HDAC) inhibitor in patients with advanced solid tumours
Rebecca Kristeleit1, Andre Brunetto1, David Olmos1, Ann Parker1, Joo-Ern Ang1, Shahneen Sandhu1, Craig Carden1, Rhoda Molife1, Bernd Hentsch2, A Mais2, B Hauns2, Johann De-Bono1
1Royal Marsden Hospital, Sutton, UK, 24SC AG, Planegg-Martinsreid, Germany
Background
4SC-201 is a potent, pan-HDAC inhibitor under evaluation as mono or combination therapy for solid and haematological malignancies. Preclinical studies of 4SC-201 demonstrated activity in a wide range of tumour cell lines and dose-dependent efficacy in xenograft studies. In combination, 4SC-201 augmented the anti-tumour activity of several approved anticancer drugs.
Method
Patients (pts) with advanced refractory solid tumours were dosed once daily,
days(d) 1-5, in a 14-d cycle in 3-6 pt cohorts dose incrementing by 50% or
100%. Primary objectives: safety, tolerability, pharmacokinetics (PK) and
maximum tolerated dose (MTD) of 4SC-201. Secondary objectives: antitumour
activity and biomarker assessment (histone acetylation and HDAC enzyme
activity).
Results
18 pts with a median age of 58.5 years (range 40-70) were treated at five dose levels ranging from 100-800mg. All pts were evaluable for toxicity and received at least 2 treatment cycles. 1 pt treated at 800mg had Grade 3 DLT of nausea and vomiting. Most common adverse events included nausea, vomiting and fatigue. 8/9 pts treated at 600mg and 800mg had stable disease during the main study phase (4 cycles). One pt with metastatic thymoma received 18 treatment cycles had a minor response and stopped without evidence of progressive disease. A patient with liposarcoma remains on treatment for over a year. Dose-proportional PK with low inter-patient variability at all dose levels (t1/2 2.3-4.4 hours) was observed. HDAC inhibition measured in a peripheral blood mononuclear cell functional assay was dose-dependent and increased from 50-100%. Increase in histone H4 acetylation did not differ significantly between dose levels.
Conclusion
4SC-201 has favourable oral bioavailability and tolerability at doses that modulate HDAC activity. 2/18 patients experienced prolonged stable disease (over 9 months). The recommended Phase II dose is 600mg, d1-5 in a 14-d cycle. Phase II single agent and combination studies are planned.
