Date: 2012-12-12
Type of information: Interim results
phase: 1-2
Announcement: interim results
Company: 4SC (Germany)
Product: resminostat (oral pan-histone deacetylase (HDAC) inhibitor)
Action
mechanism: enzyme inhibitor/histone deacetylase inhibitor. This oral pan-histone-deacetylase (HDAC) inhibitor with an innovative epigenetic mechanism of action could be deployed as a novel, targeted tumour therapy for a broad spectrum of oncological indications, both as a monotherapy and in combination with other cancer drugs. By causing structural changes to DNA, resminostat triggers a differentiation in tumour cells, can induce programmed cell death in cancer cells (apoptosis) and is able to halt tumour growth. Additionally, resminostat induces what is known as tumour cell 'resensitisation' to the treatment with other drugs. This resensitisation process can suppress or reverse drug tolerance mechanisms that tumour cells often develop against other cancer drugs and are catalysed by HDAC enzymes. Accordingly, supplementary treatment with an HDAC inhibitor such as resminostat can thus restore - or significantly improve - the efficacy of an initial cancer therapy.
Disease: advanced colorectal cancer
Therapeutic area: Cancer - Oncology
Country: Germany
Trial
details: SHORE is a randomised, open-label, multi-centre, two-arm Phase I/II study in approximately 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 (Phase I part), evaluating 200mg, 400mg, 600mg and 800mg of reminostat together with FOLFIRI.
In the combination arm resminostat will be given orally over five consecutive days (days 1-5), followed by a nine day (days 6-14) treatment free period resulting in treatment cycles of 14 days (5+9 scheme) each. FOLFIRI will be given on day three and four (days 3 and 4) 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 several centres in Germany.
The primary endpoint of the second part of the study (Phase II) 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.
Latest
news: * On December 12, 2012, 4SC has published positive interim results on safety, tolerability and pharmacokinetics from its clinical Phase I/II SHORE study with resminostat in combination treatment with FOLFIRI chemotherapy in patients with advanced colorectal cancer (CRC). The results successfully prove the safety and tolerability of the combined administration of resminostat and FOLFIRI. This marks the achievement of the goal for the first part of the study (Phase I) and lays the foundations for commencing the study's Phase II part, which will assess the clinical efficacy of the resminostat-FOLFIRI-combination in advanced CRC patients.
Furthermore, the Phase I part of the study has already provided some initial encouraging data concerning the possible cl inical benefit of this new therapeutic approach in this difficult-to-treat patient population. These data showed that for some patients it was possible to administer the combination therapy over a comparatively long period of time - to a maximum of 33 weeks - while observing a stabilisation of the tumour disease. In the Phase I part of the SHORE study, a dose escalation for a total of 15 CRC patients to date was carried out to assess the safety and tolerability of a range of doses for resminostat up to 600 mg daily in combination with FOLFIRI, a multi-component chemotherapy regime that includes e.g. 5-fluorouracil (5-FU) and irinotecan, so as to determine the best possible dose for resminostat in combination with FOLFIRI. Pharmacokinetic parameters for resminostat and for the FOLFIRI components were also evaluated.
Resminostat proved to be generally safe and well-tolerated in all doses tested up to a daily single dosage of 600 mg in combination with the recommended standard dose from the FOLFIRI regime. Accordingly, as regards combination therapy with FOLFIRI, the data confirmed the daily dosage of 600 mg already determined in earlier monotherapy and combination therapy studies with resminostat. Observed side effects were generally mild to moderate and occurred, as expected, primarily as gastrointestinal and haematological effects. FOLFIRI's known side-effect profile did not change as a result of the additional administration of resminostat. Furthermore, the study confirmed the compound's favourable pharmacokinetic profile which is, inter alia, reflected in the dose proportionality of resminostat blood levels - as already observed in other studies with resminostat. No pharmacological interactions were observed between resminostat and the FOLFIRI components. The dosage of 600 mg for resminostat in combination with FOLFIRI is already being considered as a potential therapeutic dose for the Phase II part of the SHORE study.
In some patients in the Phase I part, it was possible to administer the combination therapy for several months (to a maximum of 33 weeks) while observing stabilisation of the tumour disease. This substantiates the overall good tolerability and may also be considered as an initial indicator for the clinical benefit of this new therapeutic approach.
To allow for further expansion of the range of treatment options within this combination approach, a final, further dosage variant constituting the twice-daily administration of resminostat is currently under evaluation. This involves the clinical examination of a total daily dose of 800 mg of resminostat, taken as two doses of 400 mg in the morning and evening.
The medical-scientific rationale of the combination therapy of the epigenetically-active HDAC inhibitor resminostat - which can exert a substantial influence on key gene expressions - with traditional chemotherapy such as FOLFIRI, has been established on the basis of preclinical trials. In these studies, resminostat combined with irinotecan, a component of the FOLFIRI regime, inhibited tumour growth more effectively than either substance when used as a monotherapy. It was also shown that resminostat - due to its gene regulatory properties - decreases the expression of the enzyme thymidylate synthase. This enzyme triggers resistance mechanisms that target the compound 5-FU, which is an integral part of FOLFIRI. Accordingly, resminostat may work to sensitise tumour cells for treatment regimes containing 5-FU, such as FOLFIRI, as resminostat can be used to combat resistances that tumours have developed against 5-FU.
In the randomised, multi-centre, two-arm Phase II part of the SHORE study, planned to start soon in 2013, the combination therapy of resminostat with the FOLFIRI treatment regime will be assessed against sole treatment with FOLFIRI as a second-line treatment option for patients with advanced, KRAS-mutant colorectal cancer. For this patient group, which constitutes around 40% of all patients with advanced CRC, there is a high medical need for new, additional therapy options.
4SC is currently in discussions with regulatory agencies and potential partners in order to prepare a pivotal clinical study programme for resminostat in combination with sorafenib as a second-line treatment for patients with advanced HCC who show tumour progression on first-line treatment with sorafenib.
* On January 19, 2011, 4SC AG has announced the dosage of the first patient 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.
