4SC AG has announced that the first patient has been dosed in the Phase I/II SHORE study with the oral pan-histone deacetylase (HDAC) inhibitor resminostat as a second-line treatment for patients with advanced and metastatic colorectal KRAS-mutant cancer.
SHORE is a randomised, open-label, multi-centre, two-arm Phase I/II study in 70 patients that will evaluate the efficacy, safety and pharmacokinetics of resminostat, in combination with FOLFIRI, a chemotherapy regimen for the treatment of colorectal cancer, versus FOLFIRI alone in the control arm. In the combination arm of the study patients will be treated with the maximum tolerated dose of resminostat in combination with FOLFIRI, which will be determined through an initial dose-escalation phase, evaluating 200mg, 400mg, 600mg and 800mg of reminostat together with FOLFIRI in approximately 20 patients.
An optional extension to this dosing scheme has been included to also evaluate 300mg, 500mg and 700mg of reminostat once daily, as well as 300mg and 400mg resminostat twice daily, each dose in combination with FOLFIRI. In the combination arm resminostat will be given orally over five consecutive days (d1-5), followed by a nine day (d6-14) treatment free period resulting in treatment cycles of 14 days (5+9 scheme) each. FOLFIRI will be given on day three and four (d3 and d4) of each of these 14 day treatment cycles. In both study arms, treatment may continue until there is evidence of progressive disease or the patient leaves the trial for other reasons. The study will be performed at approximatelyten centres in Germany.
The primary endpoint of the study is to determine the progression free survival (PFS). The secondary endpoints include progression free survival rate (PFSR) after eight weeks and every eight weeks thereafter, the analysis of time-to-progression (TTP), overall survival (OS), analysis of drug safety, tolerability, pharmacokinetics and the investigation of biomarkers.
In recent years it has been discovered that colorectal cancer patients with KRAS mutant tumours do not respond to treatment with EGFR inhibitors. This has changed treatment practices, resulting in treatment with EGFR inhibitors targeting only patients with KRAS wild type tumours. As a result, a new treatment need has arisen for patients that carry mutated KRAS genes, which account for approximately 40% of metastatic colorectal cancer patients.
HDAC enzymes have emerged as promising targets in colorectal cancer over the last decade, since they have proven to be important for colon cancer cell survival. Based on both in vitro and in vivo testing it has been shown that especially the frequently observed high expression of HDAC-2 in colon cancer cells is associated with their enhanced survival capability. Resminostat, as a pan-HDAC inhibitor, reduces the activity of a variety of HDAC enzymes, including HDAC-2. Consequently, resminostat yielded promising results in preclinical models of colorectal cancer, as it also sensitized colorectal cancer cells to standard chemotherapeutics.
“By evaluating the efficacy of resminostat in patients carrying KRAS-mutant tumours, we hope to open a second-line treatment option for this colorectal cancer patient population where there is an increased unmet medical need since they cannot be treated with current EGFR targeting agents,” stated Bernd Hentsch, Chief Development Officer.
“With the commencement of the SHORE study we have delivered on our clinical development strategy for resminostat, which is assessing its efficacy in mono- and combination therapy in hematological and solid tumours. We are very excited about 2011, as we expect Phase II results for both the hepatocellular cancer SHELTER study and the Hodgkin’s lymphoma SAPHIRE study.”