4SC announces positive interim results from clinical Phase I/II trial with anti-cancer compound resminostat in colorectal cancer

(PresseBox) (Planegg-Martinsried, Germany, ) .
- Resminostat in combination with FOLFIRI chemotherapy clinically investigated as a potential new therapy option for patients with advanced colorectal cancer
- Trial objective for Phase I part of SHORE study achieved
- Safety and tolerability of the combined administration of resminostat and FOLFIRI successfully proven
- Good pharmacokinetic profile of resminostat confirmed in combination with FOLFIRI
- Initial signs for potential clinical treatment benefit: Combination therapy administered for up to 33 weeks with observed stabilisation of tumour disease
- Phase II part of study planned to start soon in 2013

4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, today published positive interim results on safety, tolerability and pharmacokinetics from its clinical Phase I/II SHORE study with the anti-cancer compound 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 clinical 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 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 (CRC). 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.

In general, first-line therapy for advanced CRC patients consists of chemotherapy (FOLFOX or FOLFIRI) in combination with the drug Avastin(R). If, after a while, this therapy is no longer effective or tolerated - due to the development of resistance or the occurrence of side effects, for example - patients are switched over to second-line therapy. In second-line, patients without a KRAS mutation have access to treatments aiming at the inhibition of epidermal growth factor receptor (EGFR) such as Erbitux(R) as a supplement to a further chemotherapy (FOLFIRI or FOLFOX). However, CRC patients with a KRAS mutation in the EGFR pathway of their tumours, generally do not benefit from anti-EGFR therapy and, therefore, receive a chemotherapy such as FOLFIRI alone as second-line therapy. Thus, for this KRAS-mutant CRC patient group there is a high medical need for new, supplementary therapy options which may be safely combined as second-line treatment with chemotherapy such as FOLFIRI to increase the latter's effectiveness - such as potentially resminostat.

Results from the Phase I part of the SHORE study

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.

Dr Ulrich Dauer, Chief Executive Officer of 4SC, commented: 'We are pleased that the good safety and tolerability profile shown by resminostat in multiple Phase I and II studies has up to now also been confirmed in combination therapy with the FOLFIRI chemotherapy, and that we have already been able to treat some patients with advanced CRC over a period of several months with this new approach. We are particularly encouraged by the disease stabilization observed in individual patients. From our perspective, this constitutes a promising new therapeutic option for potential use in combination with FOLFIRI whose clinical efficacy we will now continue to evaluate next year in the randomised Phase II part of the SHORE study. K-RAS mutant patients, who account for 40% of all CRC patients, might particularly benefit from this additional therapeutic option since they have no access to EGFR-based therapies such as Erbitux(R) as a supplementary treatment to chemotherapeutics such as FOLFIRI in second-line CRC therapy.'

About the design of the SHORE study

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.

About colorectal cancer (CRC)

Colorectal cancer (CRC) is one of the most frequently diagnosed malignant tumours of the digestive system. In Western countries, the number of cases is steadily increasing and colorectal cancer is already the second leading cause of death from cancers. Less than 7% of patients suffering from advanced, metastasized colorectal cancer survive the first five years following diagnosis of the disease.

The treatment of advanced colorectal cancer is usually based on chemotherapy regimens, such as FOLFIRI and FOLFOX, in combination with antibodies such as bevacizumab (Avastin(R)), cetuximab (Erbitux(R)) or panitumumab (Vectibix(R)). These antibodies inhibit various growth factors or receptors that are involved in the progress of the cancer disease. Currently, these approaches focus on targeting the vascular endothelial growth factor (VEGF), an angiogenic signalling protein, or on inhibiting the epidermal growth factor receptor (EGFR). However, tumours can develop tolerances to these drugs in the form of defence mechanisms that then neutralise the efficacy of the medication. Such tolerances can be combated effectively by utilising resminostat as part of combination therapy. Resminostat's epigenetic mechanism enables it to re-sensitise tumours, thus ensuring they remain treatable by other drugs.

Furthermore, for CRC patients with K-ras mutated tumours in particular, there is a specific unmet medical need since therapy options that target EGFR - such as cetuximab - cannot be utilised for such patients. As a result, there is substantial medical and commercial potential for an innovative therapeutic approach such as resminostat, even as a second-line treatment option, e.g. in combination treatment with FOLFIRI. This patient group accounts for approximately 40% of all metastatic colorectal cancer patients.

About Resminostat

Resminostat (4SC-201), 4SC's lead oncology compound, is an oral pan-histone-deacetylase (HDAC) inhibitor with an innovative epigenetic mechanism of action that potentially enables the compound to be deployed as a novel, targeted tumour therapy for a broad spectrum of oncological indications, both as a monotherapy and, in particular, in combination with other cancer drugs. HDAC inhibitors have been shown to modify the chromatin structure, which is the three-dimensional array of the genetic information DNA, () in tumour cells. This may cause a cell differentiation and eventually lead to the programmed cell death (apoptosis) of tumour cells. Therefore HDAC inhibitors are considered to offer a mechanism of action that has the particular potential to halt tumour progression and induce tumour regression. Additionally, resminostat is also assumed to induce what is known as tumour cell sensitisation to other anti-cancer compounds. This process can suppress or reverse certain tolerance and resistance mechanisms which tumour cells often develop against other cancer drugs. Supplementary treatment with resminostat can be expected to restore or significantly improve the efficacy of a previously administered cancer therapy which was no longer effective; furthermore, combining resminostat and common cancer drugs right from the very beginning can also be expected to effectively enhance the success of such a treatment.

Resminostat is currently being investigated in a broad clinical Phase II programme in the three indications liver cancer (hepatocellular carcinoma, HCC), Hodgkin's Lymphoma (HL), and colorectal cancer (CRC). In the Phase II SAPHIRE trial in patients with advanced Hodgkin's Lymphoma, resminostat in monotherapy has demonstrated substantial anti-tumour activity, with an overall response rate of 35.3% and a clinical benefit in 55.9% of the patients in a heavily pre-treated patient population together with very good safety and tolerability. In the Phase I/II SHORE study, which evaluates resminostat in combination with the chemotherapeutic FOLFIRI regimen as a second-line treatment of KRAS-mutant CRC patients, initial results are expected in 2012. Furthermore, in the Phase II SHELTER study resminostat is being evaluated as monotherapy and in combination with sorafenib as a second-line treatment in advanced HCC after proven radiological disease progression under first-line sorafenib therapy. Patients receiving the resminostat/sorafenib combination therapy showed a median overall survival of 8.0 months (as reported at the annual meeting of the International Liver Cancer Association (ILCA) on 16 September 2012). As presented at the ASCO annual meeting on 4 June 2012, the resminostat/sorafenib combination therapy had shown a progression-free survival rate (PFSR) after 12 weeks of 70.0% and a median PFS of 4.7 months. The primary study endpoint has been achieved ahead of schedule in both the combination and the monotherapy group.

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.

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